Rozprawy doktorskie: „COMT”

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Gonçalves, Ana Margarida Ribeiro. "Isoformas da enzima catecol-O-metiltransferase como alvo farmacológico na doença de Parkinson". Master's thesis, Universidade da Beira Interior, 2013. http://hdl.handle.net/10400.6/1636.

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Este trabalho encontra-se dividido em dois Capítulos. O Capítulo 1 aborda o estágio realizado em Farmácia Comunitária, na Farmácia Ferrer de Castelo Branco. Para além de serem descritas as instalações e a sua organização espacial, é apresentada a equipa técnica juntamente com suas funções e abordado de forma geral o sistema informático utilizado (Sifarma 2000). São ainda descritas as várias atividades realizadas durante o estágio, desde a elaboração de encomendas, receção e armazenamento, prestação de cuidados farmacêuticos, elaboração de medicamentos manipulados, dispensa de medicamentos sujeitos e não sujeitos a receita médica, faturação, entre outros. A legislação farmacêutica, implicada na prática farmacêutica é explorada também neste capítulo. O Capítulo 2, aborda uma revisão bibliográfica sobre as isoformas da enzima catecol-O-metiltransferase como alvo farmacológico na doença de Parkinson. A doença de Parkinson é uma doença neurodegenerativa, na qual está envolvida a perda dos neurónios dopaminérgicos da substancia nigra (pars compacta). Afeta cerca de 1% da população mundial com mais de 65 anos e pensa-se que fatores genéticos e ambientais estejam na sua origem. A catecol-O-metiltransferase (COMT) está presente tanto em eucarióticos, como em procarióticos. É uma proteína intracelular e nos mamíferos encontra-se distribuída uniformemente pelo organismo, apresentando maior atividade no fígado, rim e trato gastrointestinal. Tem como função, o metabolismo de moléculas com estrutura catecólica biologicamente ativas, sejam elas endógenas ou exógenas. Apresenta vários polimorfismos, sendo que o polimorfismo em que está implicada a substituição de Valina por Metionina é o único em que a função é conhecida. Manifesta-se na forma de duas isoformas, a forma solúvel (S-COMT) e a forma membranar (MB-COMT), sendo a forma solúvel a mais predominante no organismo, com exceção do cérebro. Para além da distribuição no organismo, elas diferem também na localização subcelular, propriedades cinéticas, especificidade com o substrato e peso molecular. A levodopa é considerada a terapêutica mais eficaz na doença de Parkinson, desde a década de 60. É administrada com inibidores da descarboxilase de ácidos aminados aromáticos (DAAA). Em doentes que apresentem flutuações motoras, são co-administrados inibidores da COMT. Atualmente o entacapone é o inibidor mais utilizado, no entanto, o opicapone, em Fase III dos ensaios clínicos, apresenta uma maior inibição, sendo que é necessária apenas uma única dose diária, ao contrário do entacapone.
This work is divided in two chapters. Chapter I covers the stage held in Community Pharmacy, on Pharmacy Ferrer - Castelo Branco. Besides describing the facilities and their spatial organization, the technical team and its functions, there is an approach to the informatics system used (Sifarma 2000), and there are also described the various activities carried out during the stage, from the ordering process, reception and storage, providing pharmaceutical care, preparation of compounded medications, dispensing prescribed and non-prescribed medications, billing, among others. Pharmaceutical legislation, involved in pharmaceutical practice is also explored in this chapter. Chapter 2 covers a bibliographic review on the isoforms of catechol-O-metiltransferase enzyme as pharmacological target in Parkinson's disease. Parkinson's disease is a neurodegenerative disease, which is involved in the loss of dopaminergic neurons of the substantia nigra (pars compacta). It affects about 1% of the population over 65 years and it is thought that genetic and environmental factors are at their origin. The catechol-O-methyltransferase (COMT) is present in both eukaryotic and prokaryotic. It is an intracellular protein, and in mammals is distributed uniformly throughout the body, presenting highest activity in the liver, kidney and gastrointestinal tract. Its main function is the metabolism of molecules with catechol structure biologically active, whether endogenous or exogenous. Presents several polymorphisms, where the polymorphism involved in the replacement of Valine by Methionine is the only one in which the function is known. Manifests as two isoforms, the soluble form (S-COMT) and the membrane form (MB-COMT), being the soluble form more prevalent in the body, except the brain. In addition to the distribution in the body, they also differ in subcellular localization, kinetic properties, substrate specificity and molecular weight. Levodopa is considered the most effective therapy in Parkinson's disease, since the 60s. It is administered with decarboxylase inhibitors of aromatic amino acid (DAAA). In patients with motor fluctuations, is co-administered with COMT inhibitors. Currently entacapone is the only available inhibitor, however, opicapone, in the third Phase of clinical trials, presents a greater inhibition, in which a single daily dose is enough, unlike entacapone.

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Andersson, Anneli. "Katekol-O-Metyltransferas (COMT), tidigare övergrepp, gen-miljöinteraktion i förutsägelsen för våld". Thesis, Örebro universitet, Institutionen för juridik, psykologi och socialt arbete, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-42712.

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Flera kandidatgener har föreslagits spela en roll i utvecklingen av antisociala beteenden i samband med miljöfaktorer. Syftet med den föreliggande studien var därmed att undersöka sambandet mellan genen Katekol-O-Metyltransferas (COMT) och våld; och om det fanns interaktioner mellan exponering för tidigare övergrepp och COMT i samband med senare våld. Data hämtades från en Svensk populationsbaserad studie baserad på 2500 20-24 åringar. Den aktuella studien fann att beroende på vilken variant av genen man besitter, kommer man att påverkas i olika grad av negativa miljöfaktorer såsom försummelse och sexuella övergrepp i samband med våld.
Several candidate genes have been suggested to play a role in the development of antisocial behavior in association with social and environmental factors. Therefore, the purpose of the present study was to investigate the relationship between the gene Catechol-O-Methyltransferase (COMT) and violence; and to examine whether there were interactions between earlier abuse and COMT in the association of violence. Data were drawn from a Swedish population-based study including 2,500 20-24 year olds. The present study found that depending on which variant of the gene one possess, one will be affected to different degree of adverse environmental factors in association with violence.

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CASTELLANO, FILIPPO. "Funzioni Esecutive e Facial Emotion Recognition in Persone Affette da Schizofrenia: ruolo del Polimorfismo del COMT e dell'Abuso di Alcol e Sostanze". Doctoral thesis, Università degli Studi di Milano-Bicocca, 2015. http://hdl.handle.net/10281/94538.

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BACKGROUND: le caratteristiche cognitive e genetiche sono sempre più centrali nello studio della Schizofrenia. La compromissione delle Funzioni Esecutive (FE), definite come un complesso di abilità cognitive superiori attribuibili alle regioni della corteccia prefrontale, e della Facial Emotion Recognition (FER) rappresentano elementi centrali nel disturbo schizofrenico. Ad oggi, però, il paradigma del (dis)funzionamento cognitivo nella Schizofrenia poggia su studi che hanno escluso i soggetti schizofrenici con storia di abuso di sostanze (SUD), che ha mostrato un impatto peggiorativo sulla cognitività nella popolazione con disturbo da uso di sostanze. La letteratura ha inoltre negli anni definito polimorfismi potenzialmente implicati sia nella Schizofrenia sia nei disturbi da uso di alcol e sostanze, come quello (rs4680) relativo al gene della catecol-O-metiltransferasi (COMT). Viste la prevalenza del fenomeno e l’associazione fra cognition, outcome funzionale e le polimorfismi genetici, lo studio di tali correlati nei pazienti schizofrenici con abuso di sostanze costituisce una questione imprescindibile per una più puntuale stratificazione diagnostica, prognostica e dei trattamenti. SCOPO DEL LAVORO: valutare l’impatto del polimorfismo del COMT e dell’abuso di alcol e sostanze sulle performance cognitive in una popolazione di soggetti con schizofrenia. MATERIALI E METODI: si tratta di uno studio descrittivoosservazionale. Sono stati reclutati 62 soggetti (M=50; F=12) con diagnosi di Schizofrenia secondo il DSM-IV (valutata attraverso la Structured Clinical Interview for DSMIV, SCID I). Il campione è stato suddiviso a seconda della presenza o meno dell’abuso di alcol e sostanze correlato (valutato con l’Alcohol e la Drug Use Scale -AUS e DUS) in due gruppi, che sono stati poi confrontati per quanto riguarda le caratteristiche sociodemografiche e cliniche (Positive and Negative Syndrome Scale - PANSS). È stata analizzata quindi l’associazione tra condizione di abuso, polimorfismo del COMT e risultati ottenuti all’Intra-Extra Dimensional Set Shift (IED), che valuta le FE e il test di Ekman, che valuta la FER, controllando per variabili sociodemografiche e cliniche. RISULTATI: I due gruppi SKZ+SUD (n=28) e SKZ-SUD (n=34) presentano una differenza statisticamente significativa per età con media (SD) pari a 47.21 (9.41) negli abusatori e 36.04 (10.09) nei non abusatori (p<0.001). All’IED gli abusatori tendono a compiere meno errori (IED Total errors adjusted 47.32 (47.77) vs 70.59 (70.84); p=0.26), un minor numero di prove (IED Total trials adjusted 136.61 (85.65) vs 178.35 (128.02); p=0.24) per raggiungere il criterio necessario a superare gli stage e un maggior numero di stage completati (IED stages completed 7.79 (2.11) vs 6.85 (3.12); p=0.35) Al test di Ekman il gruppo degli abusatori (media=41.86 (7.50)) mostra un punteggio statisticamente più alto (p=0.02) rispetto ai non abusatori (media=35.29 (11.79). All’IED (stage completati), controllando per la PANSS, il genotipo Met-Met rispetto al genotipo Val-Val è diverso nel gruppo di abuso rispetto allo stesso confronto nel gruppo di non abuso (interazione con coefficiente -4.09 CI [-8.06, -0.13]; p=0.043): Met-Met mostra una performance peggiore rispetto a Val-Val nel gruppo di abuso. Lo stesso tipo di interazione è confermata anche per quanto riguarda il test di Ekman, pur non raggiungendo la significatività statistica (interazione con coefficiente -6.46 CI [-0.83, 13.76]; p=0.081). CONCLUSIONI: I soggetti schizofrenici con abuso si sono dimostrati tendenzialmente meno compromessi sotto il profilo neuropsicologico rispetto a quelli senza abuso. Inoltre si è evidenziata un’interazione tra il polimorfismo per il gene COMT e la condizione di abuso di alcol e sostanze per quanto riguarda le performance relative alle FE e alla FER.
BACKGROUND: cognitive and genetic features are increasingly important in the study of schizophrenia. The impairment of executive function (FE) and facial emotion recognition, are central issues in schizophrenic disease. To date, however, the paradigm of the (dis) cognitive functioning in schizophrenia is based on studies that excluded subjects with schizophrenia and a history of substance abuse (SUD)(5), which is actually a phenomenon that showed a derogatory impact on cognition in the population with substance use disorder. The literature has also over the years defined polymorphisms potentially implicated in both schizophrenia and in alcohol and substance use disorders, such as the one (rs4680) related to the gene of catechol-O-methyltransferase (COMT). Given the prevalence of the phenomenon and the association between cognition, functional outcome and genetic polymorphisms, the study of these related in schizophrenic patients with substance abuse is an important issue for a more precise stratification diagnosis, prognosis and treatment. AIM: to evaluate the impact of the COMT polymorphism and alcohol and substance abuse on cognitive performance in a population of subjects with schizophrenia. MATERIALS AND METHODS: this is a observational study. We recruited 62 subjects (M = 50, F = 12) diagnosed with schizophrenia according to DSM-IV (assessed by the Structured Clinical Interview for DSM-IV, SCID I). The sample was subdivided according to the presence or not of alcohol abuse and related substances (evaluated with the Alcohol and Drug Use Scale -Aus and DUS) into two groups (SKZ+SUD and SKZ-SUD), which were then compared with regard to socio-demographic and clinical characteristics (Positive and Negative Syndrome Scale - PANSS). It was then analysed the association between the condition of abuse, COMT polymorphism and score on Intra-Extra Dimensional Shift September (IED), which evaluates the FE and on test Ekman, evaluating the FER, controlling for socio-demographic and clinical variables. RESULTS: the two groups SKZ+SUD (n= 8) and SKZ-SUD (n = 34) show a statistically significant difference by age with mean (SD) of 47.21 (9.41) in abusers and 36.04 (10.09) in non-abusers (p <0.001). Abusers tend to make fewer errors on IED (IED errors adjusted Total 47.32 (47.77) vs 70.59 (70.84); p = 0:26), fewer trials (IED trials Total Adjusted 136.61 (85.65) vs 178.35 (128.02); p = 0:24) to reach the criterion to overcome the stage and a greater number of stages completed (IED stages completed 7.79 (2.11) vs 6.85 (3.12), p = 0:35). Abusers (mean = 41.86 (7:50)) show a score statistically higher (p = 0.02) compared with non-abusers (mean = 35.29 (11.79) on Ekman test. On IED (stage completed), checking for the PANSS, the Met-Met genotype compared with Val-Val genotype was different in the group of abuse compared with the group not abusing (interaction coefficient -4.09 CI [-8.06, -0.13]; p = 0.043): Met-Met show a worse performance than in the group of Val-Val. The same type of interaction is confirmed also with regard to the Ekman , although not reaching statistical significance (interaction with coefficient -6.46 CI [-0.83, 13.76]; p = 0.081). CONCLUSIONS: subjects with schizophrenia and substance abuse seems to be less compromised from a neuropsychological point of view than those without abuse. Furthermore it is shown an interaction between the polymorphism for COMT gene and the condition of alcohol and substance abuse with regard to the FE and FER performance.

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da, Silva Costa Isis. "Variations in EEG and motor functions related to COMT gene in patients with fibromyalgia". Doctoral thesis, Universitat de les Illes Balears, 2017. http://hdl.handle.net/10803/399443.

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La fibromialgia (FM) es un síndrome crónico caracterizado por dolor generalizado, fatiga, sueño no reparador, quejas somáticas y alteraciones afectivas y cognitivas. Aunque existe evidencia reciente indicando que las emociones negativas pueden desempeñar un papel modulatorio relevante para el mantenimiento de los síntomas de la FM, poco se conoce de la influencia de los polimorfismos genéticos sobre la función motora, el sueño y el procesamiento afectivo en fibromialgia. El objetivo principal de esta tesis fue analizar la influencia del polimorfismo val158met del gen de la COMT, que se encuentra asociado a la actividad enzimática de la degradación de catecolaminas, sobre la marcha y el equilibrio, el sueño y la regulación emocional. Para ello, se ha adoptado un enfoque multidisciplinar en el que se ha tenido en cuenta parámetros biomecánicos de la función motora, la actividad cerebral durante el sueño y durante la modulación afectiva del reflejo de sobresalto para comparar individuos que muestran bien una baja o una alta actividad de COMT (homocigotos met y portadores del alelo val, respectivamente). La función motora fue evaluada mediante el análisis de la marcha y el equilibrio con grabaciones de videos en personas sanas y pacientes con FM (estudio 1). Además, dos subgrupos de pacientes con FM basados en el polimorfismo de la COMT participaron en un registro nocturno de polisomnografía (estudio 2) y una tarea experimental con la presentación de estímulos acústicos de sobresalto durante la visualización de imágenes afectivas (estudio 3). El estudio 1 mostró que las pacientes con FM presentan una reducción significativa en los parámetros de la marcha tales como velocidad, longitud del paso y del paso completo, o la cadencia, así como déficits en el control postural y el equilibrio. El estudio 2 reveló que las pacientes con FM y baja actividad de la enzima COMT parecen estar más impactadas físicamente, más deprimidas y con peor calidad de sueño (mayor número de despertares durante la noche, mayor tiempo en la cama y sueño más fragmentado durante la fase REM) que las pacientes con FM y alta actividad de la enzima COMT. Por último, el estudio 3 mostró que las pacientes con FM y baja actividad de la enzima COMT presentan alteraciones significativas de los componentes tempranos de la actividad cerebral desencadenada por estímulos agradables y desagradables comparadas con las pacientes con FM y alta actividad de la COMT. Estos estudios sugieren: 1) que la marcha y el equilibrio se encuentran alterados en las pacientes con FM comparadas con personas sin dolor, y 2) que el sueño y el procesamiento afectivo en las pacientes con FM puede ser modulado por el polimorfismo val158met del gen de la COMT que regula la actividad enzimática de las catecolaminas. En resumen, estos hallazgos proporcionan un apoyo adicional a la idea de que los síntomas de la fibromialgia precisarían de una evaluación y de una intervención terapéutica de carácter multidimensional con el objetivo de proporcionar las óptimas condiciones para la mejora de la calidad de vida de estos pacientes. Asimismo, estos hallazgos subrayan la relevancia de considerar marcadores genéticos y neurofuncionales para una compresión más completa del síndrome de fibromialgia.
La fibromialgia (FM) és una síndrome crònica caracteritzada per dolor generalitzat, fatiga, son no reparador, queixes somàtiques i alteracions afectives i cognitives. Encara que existeixen evidències indicant que emocions negatives poden tenir un paper modulador rellevant en el manteniment dels símptomes de la FM, poc es coneix de la influència dels polimorfismes genètics sobre la funció motora, el son i el processament afectiu en la fibromiàlgia. L’objectiu principal d’aquesta tesi doctoral va ser analitzar la influència del polimorfisme val158met del gen de la COMT, que es troba associat a l’activitat enzimàtica de la degradació de les catecolamines, sobre la marxa i l’equilibri, el son i la regulació emocional. Per això, s’ha adoptat un enfocament multidisciplinari en el qual s’han tingut en conte paràmetres biomecànics de la funció motora, l’activitat cerebral durant el son i durant la modulació afectiva del reflex de sobresalt per comparar subjectes que mostren una baixa o alta activitat de COMT (homozigots met i portadors d’al·lel val, respectivament). La funció motora fou avaluada mitjançant l’anàlisi de la marxa i l’equilibri amb gravacions de video en persones sanes i en pacients amb FM (estudi 1). A més, dos grups de pacients amb FM basats en el polimorfisme de la COMT participaren en un registre polisomnogràfic nocturn (estudi 2), i en una tasca experimental ambla presència d’estímuls acústics de sobresalt durant la visualització d’imatges afectives (estudi 3). L’estudi 1 mostrà que les pacients amb FM presenten una disminució significativa en paràmetres de la marxa com són la velocitat, la longitud de cada pas i del pas complet o cadència, així com dèficits en el control postural i de l’equilibri. L’estudi 2 desvetllà que les pacients amb FM amb baixa activitat de l’enzim COMT pareixen estar més impactades físicament, més deprimides i amb pitjor qualitat de son (major nombre de despertars durant la nit, major quantitat de temps en el llit i un son més fragmentat durant la fase REM), que les pacients amb FM amb alta activitat de l’enzim COMT. Per últim, l’estudi 3 mostrà que les pacients con FM amb baixa activitat de l’enzim COMT presenten alteracions significatives en els components primerencs de l’activitat cerebral desencadenada per estímuls agradables o desagradables, comparades amb les pacients con FM amb alta activitat del COMT. Aquests estudis suggereixen: 1) la marxa i l’equilibri es troben alterats en les pacients amb FM comparades amb les persones sense dolor, i 2) que el son i el processament afectiu de les pacients amb FM port estar modulat pel polimorfisme val158met del gen del COMT que regula l’activitat enzimàtica de les catecolamines. En resum, aquests resultats remarquen encara més la idea de que els símptomes de la fibromiàlgia precisen d’una avaluació i d’una intervenció terapèutica de caràcter multidimensional amb l’objectiu de proporcionar les òptimes condicions per la millora de la qualitat de vida d’aquetes pacients. Així mateix, aquestes troballes subratllen la rellevància de considerar els marcadors genètics i neurofuncionales per a una compressió més completa de la síndrome de fibromiàlgia.
Fibromyalgia (FM) is a chronic syndrome characterized by widespread pain, fatigue, unrefreshing sleep, somatic complaints, and affective and cognitive alterations. Although there is recent evidence indicating that negative affect may play a relevant modulatory role for the maintenance of fibromyalgia symptoms, little is known about how genetic polymorphisms may influence motor function, sleep and affective processing in fibromyalgia. The major goal of the present thesis was to analyze the influence of the val158met polymorphism of the COMT gene which is associated with the enzymatic activity level of cathecolamine degradation on gait and balance, sleep and emotional regulation. For this purpose, a multidisciplinary approach taking into account biomechanical parameters of motor function and parameters of the brain activity during sleep and during affective processing was used to compare individuals displaying either low (met homozygotes) or high COMT activity (val carriers). Motor function was assessed by analyzing gait and balance through video recordings in healthy controls and FM patients (study 1). In addition, two subsamples of FM patients based on the val158met polymorphism participated in a night polysomnography recording (study 2) and an experimental task with presentation of startle noise stimuli when viewing affective pictures (study 3). Study 1 showed that FM patients display a significant reduction in gait parameters such as speed, step length and full step, cadence and etc., as well as deficits in postural control and balance. Study 2 revealed that FM patients with low-activity of the COMT enzyme appear to be more physically impacted and depressed, and to have poorer quality of sleep (greater number of awakenings during the night, longer in bed and more fragmented sleep during REM) than FM patients with high-activity of the COMT enzyme. Finally, Study 3 showed that patients with low-activity of the COMT enzyme display significant alterations of the early components of the event-related brain potentials elicited by pleasant and unpleasant stimuli as compared with FM patients displaying high COMT activity. These studies suggest: 1) that gait and balance are altered in patients with FM compared to pain-free controls, and 2) that sleep and affective processing in FM patients may be modulated by the val158met polymorphism of the COMT gene that regulates the enzyme activity of catecholamines. In summary, these findings provide further support for the notion that FM symptoms would require multidimensional assessment and intervention to provide optimal conditions for improving quality of life in these patients. Moreover, our findings underline the relevance of considering genetic and neurofunctional markers for a complete understanding of fibromyalgia.

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Barbosa, Marta Cristina Fornelos. "Sistema Nervoso Central: planeamento químico-farmacológico para obtenção de um novo alvo terapêutico para a doença de Parkinson". Master's thesis, [s.n.], 2012. http://hdl.handle.net/10284/3205.

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Trabalho apresentado à Universidade Fernando Pessoa como parte integrante dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas
O presente trabalho pretende seguir uma linha de investigação pré-laboral, mas de enorme potencial devido à possibilidade de apresentar uma significativa redução nos custos aquando do lançamento de uma nova solução terapêutica. O trabalho será desenvolvido na área do sistema nervoso central (SNC) e a doença abordada será a doença de Parkinson. No decorrer deste trabalho irá ser feito uma abordagem ao tratamento farmacológico da DP, e realizado um estudo químico-farmacológico de potenciais novos inibidores da COMT. A Doença de Parkinson (DP) é uma patologia cerebral em que ocorre morte dos neurónios numa zona do cérebro designada de substância negra. É a segunda doença neurodegenerativa mais frequente depois da doença de Alzheimer. This work intends to pursue a line of pre-employment investigation, but with great potential due to the possibility of presenting a significant cost reduction at the launch of a new therapeutic solution. The work will be developed in the area of the central nervous system (CNS) and the disease discussed will be Parkinson's disease. We will make an approach to the pharmacological treatment of PD, and we will conduct a chemical and pharmacological study of potential new COMT inhibitors. Parkinson's disease (PD) is a brain pathology in which occurs neuronal death in an area of the brain called substantia nigra. It is the second most common neurodegenerative disorder after Alzheimer's disease.

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Ho-Yue-Kuang, Séverine. "Exploration des voies de biosynthèse de l’acide férulique dans les grains et tiges de Brachypodium distachyon". Nantes, 2015. https://archive.bu.univ-nantes.fr/pollux/show/show?id=ed667b2c-bd04-465a-bea7-b1ae49162a58.

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L’acide férulique joue un rôle clé dans les parois cellulaires des Poaceae en permettant la réticulation des chaînes de polysaccharides entre elles et avec les lignines. La connaissance de sa biosynthèse peut améliorer l’usage des céréales en permettant de moduler les propriétés mécaniques des parois et leur digestibilité enzymatique. La plante modèle des Poaceae, Brachypodium distachyon, a été utilisée pour explorer les voies de synthèse de l’acide férulique. Une stratégie de génétique inverse a été mise en place afin d’étudier deux enzymes candidates, la COMT et la CCoAOMT sélectionnées pour leur capacité à produire in vitro respectivement l’acide férulique et le féruloylCoA. Ces OMT étant codées par des familles multigéniques, la sélection des gènes candidats a été basée sur des analyses phylogénétiques et transcriptomiques. Des lignées mutantes ont été obtenues par mutagenèse chimique et identifiées par TILLING pour le gène BdCOMT6. L’analyse de ces lignées a montré que BdCOMT6 est une COMT impliquée dans la synthèse des lignines des tiges et des grains de B. Distachyon. Elle ne serait pas impliquée dans la synthèse de l’acide férulique lié aux parois. Des lignées d’interférence ARN ciblant cinq gènes CCoAOMT appartenant à un clade spécifique des Poaceae ont été générées. De l’acide férulique lié aux parois a été détecté dans les tiges des plantes régénérées. L’analyse des générations suivantes est en cours pour déterminer la fonction de ces gènes. Les lignines des tiges de B. Distachyon ont été étudiées en détail ces dernières années, ce travail de doctorat a permis de caractériser pour la première fois les structures des lignines présentes dans les grains
Ferulic acid plays a key role in grass cell walls, allowing the reticulation between chains of polysaccharides and with lignins. The understanding of its biosynthesis could improve cereals end-uses in allowing the modulation of the cell wall mechanical properties and enzymatical digestibility. The model plant of Poaceae, Brachypodium distachyon, was used to explore the ferulic acid biosynthesis pathways. A reverse genetic strategy has been established to study two candidate enzymes, the COMT and the CCoAOMT selected for their capacity to produce in vitro ferulic acid and feruloylCoA respectively. Since these OMTs are encoded by multigenic families, a selection of candidate genes has been performed based on phylogenetic and transcriptomic analyses. Mutant lines have been obtained through chemical mutagenesis and identified by TILLING for the BdCOMT6 gene. The analysis of these lines showed that BdCOMT6 is a COMT involved in lignin biosynthesis in B. Distachyon stems and grains. However it would not produce the ferulic acid linked to cell walls. RNA interference lines targeting five CCoAOMT genes belonging to a Poaceae specific clade have been generated. Ferulic acid linked to stem cell walls was detected by preliminary analyses of the regenerated plants. Complementary analyses of the next generations are in progress, they will allow to determine if these CCoAOMT genes have a role in the biosynthesis of ferulic acid linked to cell wall. Lignins have been studied in details over the last few years, only stem lignins were characterized in B. Distachyon, this doctoral work allowed to precisely characterize, and for the first time, the structure of the grain lignins

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Kawa, Kevin Hideyuki, i Kevin Hideyuki Kawa. "Genetic and Neuroanatomic Factors that Influence Executive Functions in Aging". Diss., The University of Arizona, 2016. http://hdl.handle.net/10150/622974.

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In the present set of experiments, we investigated the effects of age and COMT genotypes on traditional measures of executive functions, e.g., Wisconsin Card Sorting Test (WCST; Hart et al., 1988), a battery of executive functions based on the 3 factor model (shifting, updating, inhibition) described by Miyake et al. (2000) and developed at the University of Arizona (Alexander et al., 2012), and two fMRI tasks of executive functions (shifting, updating). The results of experiment 1 showed that COMT influenced performance on several traditional measures of executive functions, with Met homozygotes outperforming Val homozygotes. However, on the WCST we did not observe less perseverative errors in Met carriers as reported previously (Barnett, Jones, Robbins, & Muller, 2007; Bruder et al., 2005; Malhotra et al., 2002; Nagel et al., 2008). According to Miyake et al. (2000), however, such tasks as the WCST may actually involve multiple executive processes, making it difficult to tease apart the different types of executive functions being measured. Furthermore, COMT may be sensitive to some aspects of executive functions and not others. To this end, in experiment 2 we investigated associations between COMT and measures of executive functions from each of the 3 domains described in Miyake et al. (2000). According to the models proposed by Bilder et al. (2004) and Cools and D’Esposito (2011), the Val allele promotes cognitive flexibility, while the Met allele promotes cognitive stability. Contrary to what we expected, Met homozygotes actually performed better than Met/Val heterozygotes but no better than Val homozygotes on one measure of updating (flexibility). Upon closer examination of the processes involved in the updating task, however, the results may not necessarily be contradictory as the task may have required greater stability than previously thought. In the fMRI experiment, although behavioral performance was largely similar between age groups and COMT genotypes on the fMRI tasks, we observed differences in activation such that younger adults and Met homozygotes showed higher levels of activation relative to older adults and Val carriers, respectively. Our results suggest that these higher levels of activation may have been relied upon to maintain similar levels of performance. Additionally, across the 3 experiments the effects of COMT indicate that an overall Met advantage cannot be assumed. Rather, the benefits of one allele compared to the other should be investigated in terms of the specific cognitive processes involved in the task at hand. Thus, it is important for future studies to continue characterizing the unity and diversity of executive functions and investigate factors that may influence these patterns behaviorally and neurally, such as age and genetics.

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Stitzinger, Johannes. "Der Einfluss genetischer Variationen im COMT Gen auf kognitive Phänotypen". Diss., lmu, 2006. http://nbn-resolving.de/urn:nbn:de:bvb:19-59417.

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Laatikainen, Linda Maria. "The role of catechol-O-methyltransferase (COMT) in hippocampal function". Thesis, University of Oxford, 2010. http://ora.ox.ac.uk/objects/uuid:d0c9e1fa-a052-4af7-aaff-00548365e024.

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Catechol-O-methyltransferase (COMT) metabolises catechol-containing compounds, including dopamine. The aim of this thesis was to investigate whether COMT is involved in hippocampal function. This thesis also explored the role of functional polymorphisms within the COMT gene in the pathogenesis of schizophrenia and schizophrenia-related phenotypes. First, as part of a study investigating the role of COMT in schizophrenia, human hippocampal COMT mRNA levels were shown to be neither altered in schizophrenia or bipolar disease, nor affected by COMT genotype. Hence, functional COMT polymorphisms do not appear to operate by altering gross COMT mRNA expression. Importantly, this study showed that COMT is expressed in the human hippocampus. Second, the role of COMT in hippocampal neurochemistry was explored by studying the effect of pharmacological COMT inhibition on catecholamines and metabolites in rat hippocampal homogenates, and extracellularly, using microdialysis. Both demonstrated that COMT modulates hippocampal dopamine metabolism. Thus, hippocampal COMT is of functional significance with respect to dopamine. Third, the effect of COMT inhibition on hippocampus-dependent behaviour was investigated. The results suggested a memory-enhancing effect of pharmacological COMT inhibition on hippocampus-dependent associative and non-associative forms of short-term memory in rats. In contrast, acute COMT inhibition appeared to have no effect on behavioural correlates of ventral hippocampal function i.e. anxiety-like behaviour. In summary, the expression of COMT mRNA in the human hippocampus, as well as the effect of COMT inhibition on rat hippocampal neurochemistry and hippocampus-dependent behaviour provide evidence for a functional role of COMT in the hippocampus. Moreover, changes in COMT activity alter hippocampal dopamine metabolism, which could be a potential mechanism for the role of COMT in hippocampus-dependent short-term memory.

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Soares, Rui Filipe Lopes. "Biosynthesis of human membrane-bound Catechol-O-methyltransferase: optimization using Plackett-Burman and Central Composite Design". Master's thesis, Universidade da Beira Interior, 2012. http://hdl.handle.net/10400.6/1120.

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Catechol-O-methyltransferase (COMT, EC 2.1.1.6) is an S-adenosyl-L-methionine-dependent methyltransferase enzyme that catalyzes the methylation of catechol substrates (catecholamines, catecholestrogens). Physiologically, it is responsible for the elimination of biologically active or toxic catechols, making it a protein with great clinical relevance as therapeutic target in serious disorders, like schizophrenia and Parkinson´s disease. To fulfill pharmaceuticals requirements, new strategies of optimization and large-scale production of COMT enzyme are crucial. Statistical optimization approaches have demonstrated their enormous value in laboratory and industrial scale, namely in biotechnological production processes, in which an incremental enhancement can be a perpetual improvement. In this work, we aimed the optimization of recombinant human membrane-bound COMT (hMBCOMT) enzymatic activity yields following a statistical optimization as a solving approach. Plackett-Burman design was used as a first optimization step to identify which factors have a significant effect in hMBCOMT productivity and activity levels, and Response Surface Methodology (RSM), by a Central Composite Design (CCD), to optimize the process. We applied Brevibacillus choshinensis cells for the biosynthesis of hMBCOMT and a semi-defined medium for cell growth. This medium was subjected to a first screening using the Plackett–Burman design to evaluate the influence of the culture parameters (chemicals and physicals) in hMBCOMT enzymatic activity levels. Enzymatic activity were measured in a high performance liquid chromatography (HPLC) coupled to a coulochemical detector. Among the eleven variables tested, polypeptone, ammonium sulfate, glucose and temperature were selected owing to their significant effect on human MBCOMT enzymatic activity. The biological human MBCOMT activity obtained with the semi-defined medium in Plackett-Burman design were very promising, while were higher than the obtained with 2SYNm medium, a traditional growth medium for Brevibacillus cells of this work. Typically, we obtained values of 93nmol/h for hMBCOMT total enzymatic activity and 30 nmol/h/mg of specific activity with protein in its native form, without the use of any kind of detergents on protein solubilization step. Based on the results of Plackett–Burman design, a CCD was adopted to define optimal components concentration and temperature in order to maximize our response. The CCD model presented a multiple correlation coefficient value of 0.635 and a significant lack of fit, showing the lack aptness of the model to the process optimization and the failure to attain the optimal concentration of each variable.
Catecol-O-metiltransferase (COMT, CE 2.1.1.6) é uma enzima metiltransferase dependente de S-adenosil-L-metionina (SAM) que catalisa a metilação de substratos catecóis (catecolaminas, catecolestrogénios). Fisiologicamente, é responsável pela eliminação de catecóis biologicamente activos ou tóxicos, tornando-a uma proteína de elevado interesse clínico e utilizada como alvo terapêutico em doenças graves, como a esquizofrenia e a doença de Parkinson. Para suprir as necessidades farmacêuticas, novas estratégias de otimização e produção em larga escala desta enzima são fundamentais. Abordagens de otimização estatística têm demonstrado o seu enorme valor à escala laboratorial e industrial, nomeadamente nos processos de produção biotecnológicos, em que um pequeno detalhe melhorado pode significar um grande passo para o sucesso. Neste trabalho, objetivou-se a otimização do nível de atividade enzimática da proteína recombinante COMT, na sua forma membranar, através do recurso a modelos de otimização estatística como uma abordagem resolutiva. Numa primeira fase de otimização e de seleção dos fatores mais significativos para a atividade enzimática da proteína em estudo foi utilizada a técnica de desenho experimental Plackett-Burman. Após esta seleção foi aplicada a Metodologia de Superfície de Resposta (RSM), através de desenho composto central (DCC), para otimização da concentração dos fatores que revelaram ser mais significativos e, consequentemente, do processo. Foi utilizado o sistema de expressão Brevibacillus choshinensis para a biossíntese da proteína membranar COMT e um meio semi-definido para o seu crescimento. Este meio foi submetido a uma primeira triagem através do desenho experimental Plackett-Burman, avaliando-se desta forma a influência dos parâmetros de cultura (produtos químicos e físicos) nos níveis de actividade enzimática da COMT membranar. Os níveis de actividade enzimática foram medidos num sistema de cromatografia líquida de alta eficiência acoplado a um detector amperométrico. Entre as onze variáveis testadas, a polipeptona, sulfato de amónio, glucose e temperatura foram as variáveis selecionadas dado o seu significativo efeito na actividade enzimática da COMT membranar. Os níveis de atividade enzimática obtidos nesta primeira triagem revelaram-se bastante promissores, sendo mais elevados do que os obtidos com o meio 2SYNm, meio de crescimento mais comum para as células usadas neste trabalho. Foram obtidos valores de 93nmol/h para a actividade enzimática total e cerca 30 nmol/h/mg de actividade enzimática específica com a proteína na sua forma nativa, sem o uso de qualquer tipo de detergentes no processo de solubilização. Com base nos resultados do desenho Plackett Burman foi aplicado o desenho Composto Central para a otimização dos quatro fatores em causa a fim de maximizar a nossa resposta. Este apresentou um valor do coeficiente de correlação múltipla de 0,635 e uma falta de ajuste significativa, demonstrando a falta de adequação do modelo para a otimização do processo.

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Sutela, S. (Suvi). "Genetically modified silver birch and hybrid aspen:target and non-target effects of introduced traits". Doctoral thesis, Oulun yliopisto, 2014. http://urn.fi/urn:isbn:9789526206844.

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Abstract The efforts to improve forest trees could be accelerated by means of genetic engineering. Thus, the performance and effects of genetically modified (GM) trees have been investigated in numerous studies, which have generally concluded that GM trees have similar effects on environment and/or other organisms as do conventionally bred trees. In the present study, GM silver birch (Betula pendula Roth) and hybrid aspen (Populus tremula L. × tremuloides Michx.) lines were utilized to study the influence of transgenes to the transcription of related endogenous genes and to the production of soluble phenolic compounds in relation to ectomycorrhizal symbiosis or herbivory. The GM silver birch lines had altered lignin composition, whereas the hybrid aspen lines produced the hemoglobin of Vitreoscilla sp. (VHb). The Pt4CL1a lines were generated using biolistic transformation and monitored under greenhouse conditions for three growing seasons. The Pt4CL1a and PtCOMT silver birch lines, with altered lignin syringyl/guaiacyl ratio, had also reduced transcript levels of endogenous genes, Bp4CL1 and BpCOMT, respectively. This indicates that these members of the 4CL and COMT multigene families are likely to contribute to the monolignol biosynthesis pathway of silver birch. No unintended effects were detected in the PtCOMT or Pt4CL1a lines in relation to ECM symbiosis or performance of insect larvae. Moreover, in soluble phenolic compounds, alterations were found mainly in cinnamic acid derivatives, a group of compounds involved in the biosynthesis of monolignols. In addition, the responses of the studied hybrid aspen lines that were exposed to herbivory for 24 hours were found to be comparable. Furthermore, the proportional weight gain of lepidopteran larvae was alike when fed with leaves of the VHb and non-transgenic hybrid aspen lines. Taken together, no unintended changes were found in the GM silver birch lines with altered lignin composition or in the VHb hybrid aspen lines. However, it is acknowledged that these short-term studies that were conducted under controlled conditions have certain limitations
Tiivistelmä Puiden ominaisuuksia on mahdollista muuttaa geenitekniikkaa käyttämällä huomattavasti perinteistä jalostusta nopeammin. Geneettisen muuntamisen vaikutuksia puiden ominaisuuksiin ja vuorovaikutussuhteisiin on selvitetty useissa tutkimuksissa geenitekniikkaan liitettyjen riskien arvioimiseksi. Muunnettuja kohdeominaisuuksiaan lukuun ottamatta geneettisesti muunnettujen (GM) puiden ei ole yleisesti ottaen tutkimuksissa havaittu eroavan ympäristövaikutuksiltaan perinteisellä jalostuksella tuotetuista puista. Tässä työssä tutkittiin siirrettyjen geenien vaikutuksia GM-rauduskoivun (Betula pendula Roth) sekä hybridihaavan (Populus tremula L. × tremuloides Michx.) endogeenisten geenituotteiden ja liukoisten fenoliyhdisteiden määriin. Lisäksi työssä tarkasteltiin ligniinirakenteeltaan muunnettujen rauduskoivulinjojen ektomykorritsasymbioosia sekä ligniinimuunnettujen ja Vitreoscilla sp. -bakteerin hemoglobiinia (VHb) tuottavien hybridihaapalinjojen lehtien laatua perhostoukkien ravintona. Biolistisella geeninsiirrolla tuotetuista Amerikan haavan 4-kumaraattikoentsyymi A-ligaasi -geeniä (Pt4CL1) ilmentävistä rauduskoivulinjoista yhdessä havaittiin ligniinin syringyyli- ja guaiasyyliyksikköjen suhteessa muutos. Havaittu muutos aiheutui todennäköisesti koivun Bp4CL1-geenituotteiden määrän vähenemisestä. Myös kaffeaatti/5-hydroksylaatti O-metyylitransferaasi -geeniä (PtCOMT) ilmentävissä, ligniinirakenteeltaan muunnetuissa rauduskoivulinjoissa havaittiin endogeenisen BpCOMT-geenin tuotteiden määrän väheneminen. Tulokset viittaavat siihen, että Bp4CL1- ja BpCOMT-geenien tuottamat entsyymit toimivat rauduskoivun monolignolien biosynteesissä. Ligniiniominaisuuksiltaan muunnettujen rauduskoivujen liukoisista fenoliyhdisteistä todettiin muutoksia ensisijaisesti kanelihappojohdannaisissa, jotka liittyvät läheisesti monolignolien biosynteesireittiin. Ektomykorritsasymbioosissa tai perhostoukkien kasvunopeudessa ei havaittu kasvien geneettisestä muuntamisesta johtuvia eroja. Merkitseviä eroja ei todettu myöskään hybridihaapalinjojen herbivoria-vasteissa. On kuitenkin otettava huomioon, että kaikki tutkimuksen kokeet suoritettiin kasvihuoneissa käyttäen vasta juveniilivaiheessa olevia kasveja. Jotta abioottisten ja bioottisten ympäristötekijöiden sekä GM-puiden vuorovaikutusta olisi mahdollista arvioida kokonaisvaltaisesti, puita pitäisi tutkia pitkäaikaisissa kenttäkokeissa

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CRUZ, F. T. "Caracterização Bioquímica e Estrutural da Proteína Catecol O-metiltransferase (COMT) Como Potencial Alvo para Drogas Contra Paracoccidioidomicose". Universidade Federal do Espírito Santo, 2018. http://repositorio.ufes.br/handle/10/7868.

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A paracoccidioidomicose (PCM), micose sistêmica causada por fungos do gênero Paracoccidioides, é endêmica na América Latina, sendo o Brasil o país mais afetado. Atualmente, o tratamento com os antifúngicos tradicionais é usualmente longo, de alto custo, restrito a poucas classes de fármacos e com casos de resistência já relatados. A proteína catecol O-metiltransferase (COMT), que não possui estrutura resolvida em Paracoccidioides e nem em outros fungos, catalisa a metilação de um substrato catecol utilizando S-adenosilmetionina e íons Mg2+ como cofatores e parece participar de processos importantes em fungos patogênicos. Assim, sua caracterização bioquímica e estrutural poderia contribuir para o desenvolvimento de novas drogas mais efetivas para o tratamento da PCM. Para estudar a COMT, sua sequência codificadora foi clonada no vetor pET-28aTEV, que adiciona uma cauda de histidinas (His-tag) N-terminal à proteína expressa. O vetor recombinante foi então inserido nas cepas de Escherichia coli BL21, ArcticExpress, Rosetta e Rosetta-gami. A COMT recombinante foi expressa na fração solúvel da ArcticExpress e esta foi submetida à cromatografia de afinidade ao níquel seguida de gel filtração (colunas Ultrahydrogel e Superose 12). O Western blot com anticorpo anti-Histag marcou as duas bandas principais observadas no SDS-PAGE (30 e 60 kDa) da fração obtida após a afinidade. O perfil da gel filtração apresentou três picos principais (frações 1, 2 e 3) que, em SDS-PAGE, mostraram a presença de uma banda proeminente próxima a 60 kDa. As amostras das três frações foram utilizadas em ensaio de atividade para avaliar o consumo de catecol a 35 ºC e pH 7,5 sendo que a fração 2 apresentou maior relação atividade/quantidade de proteína. Cálculos teóricos das massas referentes aos picos da cromatografia de gel filtração indicam que a COMT se comporta como um dímero. A fração 2, apesar de não estar pura, foi submetida a ensaio de desnaturação térmica, onde um processo de agregação ou desnaturação foi detectado em temperaturas acima de 320 K (~47 ºC). O dicroísmo circular da fração 2 indicou um perfil de α-hélice e folhas-β diferente de outras COMT. Um modelo in silico também foi gerado e os dados estruturais obtidos podem contribuir como guia para futuras caracterizações bioquímicas. PALAVRAS-CHAVE: Paracoccidioides, Paracoccidioidomicose, PCM, catecol O-metiltransferase, COMT.

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Meloto, Carolina Beraldo 1983. "Caracterização de uma nova isoforma da enzima COMT associada à DTM". [s.n.], 2013. http://repositorio.unicamp.br/jspui/handle/REPOSIP/290517.

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Orientador: Célia Marisa Rizzatti Barbosa
Tese (Doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
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Resumo: Catecolamina-O-metiltransferase (COMT) é uma enzima com amplas funções biológicas, inclusive a modulação da dor, exercidas através da metabolização de substratos como a dopamina, adrenalina, e noradrenalina. Já é sabido que a atividade da COMT é geneticamente polimórfica em humanos, e se correlaciona com a percepção individual da dor e eficiência na sua remissão entre pacientes com disfunção temporomandibular (DTM) tratados com propranolol. Por isso, nosso primeiro objetivo foi investigar novos polimorfismos de nucleotídeo único (SNP) que pudessem marcar para este benefício. De fato, encontramos um novo SNP, rs165774 (G>A), que se mostrou associado à DTM ou fenótipos intermediários em duas coortes diferentes. Este polimorfismo, por sua vez, se localiza em proximidade a um segundo SNP, rs165895 (T>C), ambos na região 3' não traduzida (3'UTR) de um mRNA alternativo da COMT ainda não caracterizado. Assim, também foi nossos objetivos (i) verificar a expressão deste transcrito em diferentes tecidos humanos e linhas de células, rastreando-o por RT-PCR (Reverse Transcriptase - Polymerase Chain Reaction); (ii) predizer a estrutura cristalina da enzima codificada por ele, através de modelagem pelo método dinâmico molecular discreto; (iii) expressá-lo em um sistema celular e comparar sua expressão relativa e atividade enzimática às da isoforma convencional, determinando-as por RT-PCR e HPLC (High Performance Liquid Chromatography), respectivamente; e (iv) verificar os efeitos dos SNPs rs165774 e rs165895 sobre este transcrito, criando-se diferentes mutantes por mutação sítio-dirigida e observando seus efeitos sobre a expressão relativa e atividade enzimática. Nossos resultados mostraram que (i) o transcrito alternativo da COMT é expresso em diferentes tecidos humanos e sistemas celulares; (ii) a estrutura cristalina de sua enzima exibe uma região C-terminal único que é distinta da isoforma convencional; e que este transcrito é (iii) menos relativamente expresso e sua enzima menos ativa que o transcrito e a enzima convencionais, respectivamente, e (iv) sofre regulação em nível transcricional pelos SNPs rs165774 e rs165895. Com este estudo, pudemos concluir que o SNP rs165774 é um forte marcador genético para DTM; que juntamente com o SNP rs165895, localizam-se na região 3'UTR de uma forma alternativa de mRNA da COMT que, pela primeira vez, provou ser capaz de codificar para uma isoforma alternativa da enzima que exibe atividade enzimática; e que esta isoforma alternativa de mRNA da COMT sofre efeitos regulatórios, em nível transcricional, causados por ambos os SNPs
Abstract: Catecolamine-O-methyltransferase (COMT) is an enzyme with broad biological functions, including pain modulation, exerted through metabolization of substrates such as dopamine, epinephrine, and norepinephrine. It is well known that COMT activity is genetically polymorphic in humans, and correlates to individual pain perception and efficiency in its remission among temporomandibular disorder (TMD) patients treated with propranolol. Thus, our first aim was to investigate new single nucleotide polymorphism (SNP) that might mark for this benefit. Indeed, we have found a new SNP, rs165774 (G>A), that was associated with TMD or intermediate phenotypes in two different cohorts. This polymorphism, in turn, is in close proximity to a second SNP, rs165895 (T>C), both in the 3' untranslated region (3'UTR) of an alternative COMT mRNA that has not yet been characterized. Therefore, we also aimed to (i) verify the expression of this transcript in different human tissues and cell systems, tracking it through RT-PCR (Reverse Transcriptase - Polymerase Chain Reaction); (ii) predict the crystalline structure of the enzyme encoded by it, modeling it with discrete molecular dynamics; (iii) express it in a cell system and compare its relative expression and enzymatic activity to the conventional isoform, using RT-PCR and HPLC (High Performance Liquid Chromatography), respectively; and (iv) verify the effects of SNPs rs165774 and rs165895 on the transcript, creating different mutants by site-directed mutagenesis and observing their effects on the relative expression and enzymatic activity. Our findings show that (i) the alternative COMT transcript is expressed in different human tissues and cell systems; (ii) the crystalline structure of its enzyme exhibits a unique C-terminus that is distinct from the conventional isoform; and that this transcript is (iii) less relatively expressed and its enzyme is less active than the conventional transcript and enzyme, respectively, and (iv) is regulated, at transcriptional level, by the SNPs rs165774 e rs165895. With this study, we conclude that SNP SNPs rs165774 is a strong genetic marker for TMD; that along with SNPs rs165895, they are located in the 3'UTR of an alternative COMT mRNA which proved, for the first time, to be able of encoding an alternative isoform of the enzyme that exhibits enzymatic activity; and that this alternative COMT mRNA is regulated, at transcriptional level, by both SNPs
Doutorado
Protese Dental
Doutora em Clínica Odontológica

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Acosta, Conchucos Oscar. "Polimorfismo en el gen de la catecol o-metil transferasa (comt) y su asociacion con la esquizofrenia en una muestra peruana". Master's thesis, Universidad Nacional Mayor de San Marcos, 2015. https://hdl.handle.net/20.500.12672/4470.

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La Esquizofrenia es una enfermedad mental crónica y compleja que afecta al 1% de la población. El gen que codifica a la enzima catecol o-metil transferasa (COMT) es candidato de riesgo porque participa en el catabolismo de la dopamina. El polimorfismo funcional Val/Met (rs4680) en el gen COMT genera actividad enzimática diferencial, es variable en las poblaciones y ha sido asociado a la esquizofrenia. En el Perú, no existen estudios de asociación genética y es necesario implementarlas para la prevención, diagnóstico, pronóstico y farmacogenética de la enfermedad. El objetivo fue establecer la asociación entre el polimorfismo Val/Met en el gen COMT y la esquizofrenia en una muestra peruana. Se ha realizado un estudio tipo casos-controles, previo consentimiento informado, con una muestra de 50 pacientes esquizofrénicos del hospital nacional Hermilio Valdizán y 150 personas saludables, sin diagnóstico de la enfermedad, residentes en la ciudad de Lima. El análisis molecular del polimorfismo Val/Met se realizó mediante la técnica PCR-RFLP y confirmado por secuenciamiento automático. En los controles y los pacientes las frecuencias genotípicas fueron similares (Val/Val=40-44%, Val/Met=46-52%, Met/Met=8-10%), y evaluados según el modelo de herencia codominante, no se han encontrado diferencias significativas [p>0.05; Val/Met: OR=0.80 (IC 95%: 0.41-1.58) y Met/Met: OR=1.14 (IC 95%: 0.36-3.64)]; la tendencia es similar bajo los modelos de herencia dominante, recesivo, sobredominante y aditivo. Asimismo, las frecuencias alélicas en ambos grupos (Val=66-67%, Met=33-34%), no muestran diferencias (p>0.05). Además, el género no interactúa en la asociación con la enfermedad según genotipos Val/Met (p>0.05). Los resultados nos indican que no existe asociación entre el polimorfismo Val/Met en el gen COMT y la susceptibilidad a la esquizofrenia en esta muestra peruana evaluada. En perspectiva, es necesario estudiar un mayor número de muestra, incluir otras subpoblaciones peruanas según ancestralidad, evaluar en conjunto con otros genes y epigenes, considerar los endofenotipos clínicos y utilizar tecnologías de secuenciamiento de ADN de alto rendimiento.
Tesis

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Herndon, Joseph Menzel. "Methylenedioxymethamphetamine-Induced Neurotoxicity: The Role of Hepatic Enzymes Cytochrome P450 2D6 and Catechol-O-Methyltransferase and Contribution of Microglia". Diss., The University of Arizona, 2013. http://hdl.handle.net/10150/306920.

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3,4-(±)-Methylenedioxymethamphetamine (MDMA, ecstasy) is a widely abused amphetamine derivative. The metabolism of MDMA is thought to be a necessary component of MDMA-induced neurotoxicity, as direct administration of MDMA into the central nervous system of rats failed to reproduce the hallmark serotonin deficits seen following systemic administration of MDMA. Mechanistic questions remain regarding how MDMA elicits this neurotoxicity. Work of this thesis was undertaken to examine how MDMA-induced neurotoxicity is affected by the activity of two polymorphic enzymes involved in the metabolism of MDMA, namely cytochrome P450 family member 2D6 (CYP2D6) and catechol-O-methyltransferase (COMT), as well as the potential role microglia play in the facilitation of this neurotoxicity. Inhibition of CYP2D1, the homolog of human CYP2D6 in the rat, resulted in an attenuation of serotonergic neurotoxicity following MDMA-administration. In both a pharmacological model and a genetic model of CYP2D1 inhibition, serotonin deficits were alleviated when compared to normal-activity CYP2D1 counterparts. Inhibition of COMT, the primary detoxication enzyme in the MDMA pathway, resulted in potentiation of MDMA-induced neurotoxicity. In a pharmacological model of COMT inhibition, rats displayed greater long-term serotonin deficits after COMT inhibition. Mice devoid of COMT proved sensitive to the lethal hyperthermic effects of MDMA, illustrating the importance of this enzyme in preventing the acute toxicity of MDMA. Brain lesions often elicit a microglial response. Microglia have the potential of both beneficial and deleterious actions in the brain. Whether microglia are activated by nerve terminal degeneration produced by MDMA is an area of ongoing debate. Systemically delivered MDMA produces a modest increase in the amount of microglial cells present in the parietal cortex of rats over a one-week period. MDMA also increased the phagocytic activity of microglia in the cortex. The studies described herein support the hypothesis that metabolism is critical in MDMA-induced neurotoxicity. Furthermore, as both CYP2D6 and COMT are polymorphic in the human population, certain individuals are more at risk for severe serotonergic toxicity following MDMA administration. Finally, while microglia are likely not the cause of MDMA-induced neurotoxicity, contributions of these cells cannot be dismissed.

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Santos, Raquel Alves dos. "Polimorfismos nos Genes CYP17, CYP1B1, CYP1A1 e COMT e as Lesões Genômicas Espontâneas em Pacientes com Câncer de Mama". Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/17/17135/tde-11072008-143956/.

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O Câncer de Mama (CM) é o segundo tipo mais freqüente de câncer no mundo e a doença maligna mais comum entre as mulheres. Apesar do câncer ser considerado uma típica doença do envelhecimento, o CM apresenta algumas características distintas no que diz respeito às taxas de incidência. Os fatores de risco para o CM incluem idade da menarca precoce e menopausa tardia, terapias hormonais, exposição aos poluentes ambientais, tabagismo e etilismo, no entanto, a exposição prolongada aos estrógenos representa o fator de risco mais importante. A biossíntese e a metabolização dos estrógenos requerem um grande número de vias que são reguladas por uma série de genes cujos polimorfismos têm sido descritos em associação com o CM. Também se sabe que os estrógenos podem danificar a molécula de DNA por aumentar a formação de aductos ou ainda por induzir a 8-hidroxilação de purinas e as quebras de fita simples e duplas do DNA. Dessa forma, o objetivo do presente do presente trabalho foi investigar os níveis de danos no DNA de pacientes com CM antes da quimioterapia ou da radioterapia, a possível associação entre os polimorfismos dos genes metabolizadores de estrógeno CYP17, CYP1B1, CYP1A1 and COMT e o risco ao CM e também a possível influência desses polimorfismos nos níveis espontâneos de danos no DNA. Os linfócitos do sangue periférico de 45 mulheres com diagnóstico para Carcinoma Ductal \"in situ\" ou invasorl e 85 mulheres sadias (controles) foram utilizados para avaliação de danos espontâneos no DNA pelo teste do micronúcleo e Ensaio Cometa. Os resultados mostraram que as freqüências de micronúcleos (MNs) e os danos no DNA detectados pelo Ensaio Cometa foram significativamente maiores no grupo de pacientes do CM do que no grupo controle. Os níveis de danos no DNA foram similares entre fumantes e não-fumantes e a idade não influenciou as freqüências de MNs observadas em pacientes com CM e controles. Para a abordagem molecular a casuística foi de 131 mulheres controles saudáveis e 104 mulheres também com diagnóstico para Carcinoma ductal \"in situ\" ou invasor. A comparação da ocorrência dos polimorfismos estudados nos genes CYP17, CYP1A1 e COMT não mostrou diferenças estatisticamente significativas entre pacientes e controles. Contudo, o genótipo Leu/Leu para o gene CYP1B1 aumentou em três vezes o risco para o CM entre não-fumantes (P = 0,04, OR = 3; 95% intervalo de confiança: 1,1-8,2). Os polimorfismos estudados nos genes citados acima não tiveram associação com a idade da menarca ou da menopausa em pacientes com CM e controles. A possível associação dos polimorfismos nos genes CYP17, CYP1B1, CYP1A1 e COMT sobre os níveis de danos no DNA também foi avaliada e, enquanto o CYP17 e CYP1A1 não afetaram as freqüências de MNs ou os danos no DNA observados pelo Ensaio Cometa nem em pacientes com CM nem no grupo controle, o alelo Leu do CYP1B1 esteve significativamente associado com altos níveis de danos no DNA do grupo controle, mas não interferiu nos danos do DNA detectados no grupo com CM. Em contrapartida, no grupo controle, o indivíduos portadores do alelo Met do gene COMT exibiram níveis mais baixos de danos no DNA quando comparados com o homozigoto selvagem, mas no grupo com CM os indivíduos polimórficos homozigotos (Met/Met) apresentaram níveis de danos no DNA mais elevados do que os seu correspondentes homozigotos selvagens e heterozigotos. Concluindo, este trabalho demonstrou que mulheres com CM apresentam uma instabilidade genômica importante e sugere que os polimorfismos nos genes metabolizadores de estrógenos podem modificar os níveis de danos no DNA tanto em mulheres sadias quanto em mulheres com CM.
Breast cancer (BC) is the second most frequent kind of cancer in worldwide and the most common malignant disease among women. Although cancer is considered a typical aging disease, BC is presenting some distinctive features concerning age-specific incidence rates. Risk factors for breast cancer include early age of menarche and late menopause, hormonal therapies, exposure to environmental pollutants, smoking and alcohol habits, however, increased or prolonged estrogen exposure is the most important risk factor. Estrogen biosynthesis and metabolism requires a great number of enzymatic pathways regulated by different genes with polymorphisms that has been described in association with BC and is well known that estrogens can damage the DNA by increasing the formation of DNA adducts and by inducing 8-hidroxilation of purine bases and breaks in DNA strand. Thus, the aim of the present work was to investigate the levels of DNA damage in BC patients prior chemotherapy or radiotherapy, the possible association of the estrogen metabolizing genes CYP17, CYP1B1, CYP1A1 and COMT polymorphisms on breast cancer risk and also the possible influence of these polymorphisms on the spontaneous levels of DNA damage. Micronucleus test and Comet assay was performed to detect spontaneous DNA damage, using peripheral blood lymphocytes from 45 women diagnosed for Ductal \"in situ\" or invasive breast carcinoma and 85 healthy control women. The results showed that the micronucleus (MNs) frequencies and DNA damage detected by Comet assay were significantly higher in BC group than in controls. The levels of DNA damage were similar in smokers and non-smokers and aging did not influence the frequencies of MNs observed BC patients and in controls. For molecular approach the casuistic comprised of 131 healthy control women and 104 women also diagnosed for Ductal \"in situ\" or invasive breast carcinoma. Comparison of the occurrence of the polymorphisms in CYP17, CYP1A1 and COMT was not statistically different between patients and controls. However, the risk for BC is three-fold increased in non-smokers Leu/Leu group for CYP1B1 (P = 0,04, OR = 3; 95% confidence intervals: 1,1-8,2). The polymorphisms studied in the above mentioned genes did not influence the age of menarche or menopause differently in BC and controls. The influence of CYP17, CYP1B1, CYP1A1 and COMT polymorphisms on the levels of DNA damage was also analyzed and while CYP17 and CYP1A1 did not affect the MNs frequencies or the DNA damage observed by Comet assay in neither in BC nor in control group, the Leu allele of CYP1B1 was significantly associated with the higher levels of DNA damage in control group, but did not interfere on DNA damage detected in BC group. On the other hand in the control group, individuals carrying the Met allele of COMT exhibited lower levels of DNA damage when compared to wild type homozygous, but in BC group the polymorphic homozygous individuals (Met/Met) presented higher levels of DNA than their wild type homozygous or heterozygous counterparts. In conclusion, the present work demonstrated that BC women present an important genomic instability and suggests that estrogens metabolizing polymorphisms may modify the levels of DNA damage in healthy and in BC women.

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Leite, Daniela Batista [UNIFESP]. "Análise de polimorfismos nos genes CYP1A1, CYP17, COMT, GSTM1, receptor de estrogênios e progesterona em mulheres com carcinoma de ovário". Universidade Federal de São Paulo (UNIFESP), 2009. http://repositorio.unifesp.br/handle/11600/8921.

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Made available in DSpace on 2015-07-22T20:49:22Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-05-27. Added 1 bitstream(s) on 2015-08-11T03:26:02Z : No. of bitstreams: 1 Publico-12476a.pdf: 514198 bytes, checksum: 306e8e833c955689b74e651234403df7 (MD5). Added 1 bitstream(s) on 2015-08-11T03:26:02Z : No. of bitstreams: 2 Publico-12476a.pdf: 514198 bytes, checksum: 306e8e833c955689b74e651234403df7 (MD5) Publico-12476b.pdf: 919832 bytes, checksum: 5b5b71d4ae84bf97e482da7ae01a38c5 (MD5). Added 1 bitstream(s) on 2015-08-11T03:26:02Z : No. of bitstreams: 3 Publico-12476a.pdf: 514198 bytes, checksum: 306e8e833c955689b74e651234403df7 (MD5) Publico-12476b.pdf: 919832 bytes, checksum: 5b5b71d4ae84bf97e482da7ae01a38c5 (MD5) Publico-12476c.pdf: 500619 bytes, checksum: aefb16bdc44ab8a789985f9c1034edf1 (MD5). Added 1 bitstream(s) on 2015-08-11T03:26:02Z : No. of bitstreams: 4 Publico-12476a.pdf: 514198 bytes, checksum: 306e8e833c955689b74e651234403df7 (MD5) Publico-12476b.pdf: 919832 bytes, checksum: 5b5b71d4ae84bf97e482da7ae01a38c5 (MD5) Publico-12476c.pdf: 500619 bytes, checksum: aefb16bdc44ab8a789985f9c1034edf1 (MD5) Publico-12476d.pdf: 1713770 bytes, checksum: 199a9ecb38342412d767035889135b0c (MD5). Added 1 bitstream(s) on 2015-08-11T03:26:02Z : No. of bitstreams: 5 Publico-12476a.pdf: 514198 bytes, checksum: 306e8e833c955689b74e651234403df7 (MD5) Publico-12476b.pdf: 919832 bytes, checksum: 5b5b71d4ae84bf97e482da7ae01a38c5 (MD5) Publico-12476c.pdf: 500619 bytes, checksum: aefb16bdc44ab8a789985f9c1034edf1 (MD5) Publico-12476d.pdf: 1713770 bytes, checksum: 199a9ecb38342412d767035889135b0c (MD5) Publico-12476e.pdf: 1210097 bytes, checksum: b3add8b741a7811a237254e76a5afe6e (MD5)
Objetivos: Avaliar a associação entre os polimorfismos gênicos presentes nos genes do citocromo P450c17 (CYP17), receptor de progesterona (PROGINS) e estrógeno (ER), glutationa S-transferase (GSTM1), catecol-O-metiltransferase (COMT) e polimorfismo do citocromo P450c 1A1 (CYP1A1) em pacientes com e sem carcinoma de ovário e analisar a eventual associação dos referidos polimorfismos com as variáveis clínicas e anatomopatológicas. Métodos: Analisaram-se 103 pacientes com carcinoma de ovário atendidas no Ambulatório de Oncologia Ginecológica do Departamento de Ginecologia da Universidade Federal de São Paulo - Escola Paulista de Medicina (UNIFESP-EPM) e no Ambulatório de Oncoginecologia do Serviço de Ginecologia e Obstetrícia do Hospital do Servidor Público Estadual de São Paulo – Francisco Morato Oliveira (HSPE-FMO). O grupo controle I foi constituído por 282 pacientes e o grupo controle II por 141 pacientes atendidas no Setor de Climatério da Disciplina de Endocrinologia Ginecológica do Departamento de Ginecologia da UNIFESP-EPM. O DNA foi extraído a partir de células da mucosa oral e a genotipagem para os polimorfismos foi realizada pela técnica de PCR-RFLP. Resultados: Observamos uma associação significativa entre a frequência do polimorfismo PROGINS e o desenvolvimento do câncer de ovário (p<0,0001). Também foi observada uma associação significativa entre a frequência dos polimorfismos ER-PvuII, ER-XbaI e ER-HaeIII (p=0,03; p<0,00001 e p=0,04, respectivamente) e o desenvolvimento de câncer de ovário e uma tendência de associação entre a presença do polimorfismo ER-MspI (p=0,07) com o carcinoma. Com relação aos polimorfismos presentes nos genes do CYP17, GSTM1, COMT e CYP1A1, não foram observadas diferenças significativas entre o grupo de casos e controles ou entre as outras variáveis de risco analisadas, sugerindo que os mesmos não apresentam uma participação importante no desenvolvimento do carcinoma de ovário em nossa amostra. Não se observou nenhuma relação entre os polimorfismos estudados e TRH, dismenorréia, dispareunia, câncer de mama, hipertensão arterial, diabetes, tipo histológico, estado clínico e grau de diferenciação. Entretanto, foram observadas associações estatisticamente significantes para o polimorfismo PROGINS e antecedentes familiares (p=0,009). Conclusões: Polimorfismos presentes em genes envolvidos na ação dos esteróides sexuais, como PROGINS e ER-α parecem exercer influência no surgimento de condições patológicas como o carcinoma de ovário.
Objectives: To evaluate the association between polymorphisms of cytochrome P450c17 (CYP17), progesterone receptor (PROGINS), gluthatione S-transferase (GSTM1), Catechol-O-methyl transferase (COMT), and cytochrome P450c1A1 CYP1A1) genes in patients with and without ovarian cancer and to analyze the eventual association of these polymorphisms with clinical and pathological variables. Methods: A total of 103 ovarian cancer patients were seen at the Oncological Surgery Outpatients Clinic, Department of Gynecology - Universidade Federal de São Paulo - Escola Paulista de Medicina (UNIFESP-EPM) and at the Oncological Gynecology Outpatients Clinic, Division of Gynecology and Obstetrics, Hospital do Servidor Público Estadual de São Paulo – Francisco Morato Oliveira (HSPE-FMO). The control group I comprised 282 patients and control goroup II comprised 141 patients seen at the Climacteric Sector, Division of Gynecological Endocrinology, Department of Gynecology - UNIFESP-EPM. The DNA was extracted from oral mucosa cells and genotyping for PROGINS, GSTM1 and CYP17 polymorphism was carried out by means of PCR-RFLP. Results: A significant association was observed between frequency of PROGINS polymorphism and development of ovarian cancer (p<0.0001). Furthermore, a significant association between the frequency of polymorphisms ER-PvuII, ERXbaI e ER-HaeIII (p = 0.03, p <0.00001 and p = 0.04, respectively) and the development of ovarian cancer and a trend of association between the presence of ER-MspI polymorphism (p=0.07) with the carcinoma. Concerning CYP17, GSTM1, COMT and CYP1A1 polymorphisms, there was no statistically significant difference between the two groups. A significant association between the frequency of PROGINS polymorphism and familial antecedents was observed ((p=0.009). Conclusions: We concluded that differently from CYP17, GSTM1, COMT and CYP1A1 polymorphisms, which had no association between polymorphism and cancer, the PROGINS, ER-PvuII, ER-XbaI and ER-HaeIII polymorphisms were positively associated with ovarian cancer.
TEDE
BV UNIFESP: Teses e dissertações

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Duarte, Dante Galileu Guedes. "Estresse precoce e comportamento suicida em pacientes bipolares: estudo de associação com polimorfismos dos genes da COMT e do BDNF". Universidade Federal de Minas Gerais, 2013. http://hdl.handle.net/1843/BUOS-9AXFQE.

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The Bipolar Disorder (BD) is a psychiatric disorder associated with high rates of suicide attempts. Early life stress (ELS) one of several factors that contribute to the appearance of Suicidal Behavior and negatively influences the course of BD. There are many articles that confirm this association. We selected 47 patients with BD I, attending the Affective Disorders Clinic of the Residence of Psychiatry, Federal University of Minas Gerais (UFMG). In addition, 48 randomly selected controls by sex, age and education. Were fulfilled Hamilton depression scales, the Young Mania Scale, and a structured psychiatric interview (MINI PLUS 5.0). ELS was assessed by questionnaire on the Childhood Trauma Questionnaire (CTQ) and suicidal behavior by Beck's Suicide Scale, and the attempt lethality by Becks Lethaliy Scale. Genetic polymorphisms of COMT and BDNF were assessed by PCR. Statistical analyzes were performed using Kolmogorv-Smirnov test, the Student t test or the Mann Whitney U and the chi-square (X2) Statistical analyzes were performed using the genetic program unphased 3.0.12. Among patients with BD were divided in groups with and without ELS and groups with and without suicidal behavior there were no significant differences in any variable studied. No association was found between the allelic or genotypic SNP studied for COMT and BDNF genes with suicidal behavior and ELS. We observed a slight tendency to the higher frequency of the heterozygous genotype GA in patients without Stress Early with suicidal behavior (p = 0.06). In conclusion, this study corroborates the notion that Suicidal Behavior is the result of complex interactions between multiple variables, including genetic factors. Independent replications in larger samples and further investigation on the role of ELS in this intricate network are necessary.
O Transtorno Afetivo Bipolar (TAB) é um transtorno psiquiátrico relacionado com altas taxas de tentativas de suicídio. O Estresse precoce é um dos diversos fatores que contribuem para o aparecimento do Comportamento Suicida e influencia negativamente o curso do TAB. Há diversos artigos que corroboram essa associação. Foram selecionados 47 pacientes portadores de TAB tipo 1, que frequentam o Ambulatório de Transtornos Afetivos da Residência de Psiquiatria da Universidade Federal de Minas Gerais (UFMG). Além disso, selecionamos aleatoriamente 48 controles. Foram preenchidas as escalas de depressão de Hamilton, a escala de mania de Young, assim como uma entrevista psiquiátrica estruturada (MINI PLUS 5.0). O Estresse precoce foi avaliado pela Questionário sobre Traumas na Infância (QUESI) e o comportamento suicida pela Escala de Intenção Suicida de Beck (Becks Suicide Scale), Escala de Letalidade de Beck e avaliamos o tipo de tentativa de suicídio, se violenta ou não violentas. Os controles não foram avaliados pelas escalas, apenas pelo MINI PLUS. Polimorfismos dos genes da COMT e BDNF foram avaliados por PCR. As análises estatísticas foram feitas utilizando Kolmogorv-Smirnov, o Teste t de Student ou o teste U de Mann Whitney e o teste do qui-quadrado (X2). As análises estatísticas (genéticas) dos resultados obtidos do material foram realizadas utilizando o programa Unphased 3.0.12. Não foram observadas diferenças significativas entre os pacientes com TAB que foram divididos no grupo com Estresse precoce e sem Estresse precoce, e também quando foram comparados com presença e ausência de comportamento suicida. Não foi encontrada associação alélica ou genotípica entre o SNP estudado para os genes da COMT e BDNF com comportamento suicida e Estresse precoce. Em conclusão, este estudo corroborou com a noção de que o Comportamento Suicida é o resultado de interações complexas entre múltiplas variáveis, incluindo fatores genéticos. Contribuiu, trazendo mais conhecimento sobre o assunto e, com isso, despertando a atenção dos clínicos sobre a importância da prevenção de Comportamento suicida naqueles pacientes que sofreram Estresse precoce. Repetições independentes em amostras maiores e investigações mais aprofundadas sobre o papel do Estresse precoce nessa intrincada rede fazem-se necessárias.

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Melton, Amanda M. A. "Influence of COMT gene variant on working memory in survivors of childhood brain tumors /". Full text available from ProQuest UM Digital Dissertations, 2009. http://0-proquest.umi.com.umiss.lib.olemiss.edu/pqdweb?index=0&did=1913291401&SrchMode=1&sid=1&Fmt=2&VInst=PROD&VType=PQD&RQT=309&VName=PQD&TS=1278096109&clientId=22256.

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Ott, Cordula. "Assoziation des Single Nucleotid Polymorphismus V108/158M im COMT-Gen mit Suizidalität und Persönlichkeit". Diss., lmu, 2007. http://nbn-resolving.de/urn:nbn:de:bvb:19-79505.

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Stumpenhorst, Katharina. "Separate and interactive effects of catechol-o-methyltransferase and tetrahydrocannabinol on frontostriatal dopamine function". Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:e8eb9eba-0e32-4b30-8349-c2678207f547.

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The frontostriatal dopamine system modulates brain function and is affected by both genetic and environmental factors. Dysfunction of this system is associated with many pathological states, including schizophrenia. The enzyme catechol-O- methyltransferase (COMT) metabolises dopamine and its gene contains a polymorphism (Val¹⁵⁸Met) that affects enzyme activity. Delta-9- tetrahydrocannabinol (THC), the main psychoactive component of cannabis, has been suggested to interact with this polymorphism to increase the risk for psychosis and cognitive impairments. Dopaminergic mechanisms are a plausible candidate for mediating this interaction. I used microdialysis coupled with high performance liquid chromatography (HPLC) to examine the effects of THC on extracellular dopamine and its metabolites in the nucleus accumbens, dorsal striatum and medial prefrontal cortex (mPFC) in freely moving mice. Following acute COMT inhibition with tolcapone, THC increased extracellular dopamine levels in the nucleus accumbens in tolcapone-, but not in vehicle-, treated mice. The introduction of the low activity Met allele into the COMT gene produced a highly specific, novel mouse model of the Val158Met polymorphism. In contrast to the effects of acute COMT inhibition, the Met allele protected against THC-induced changes in accumbal dopamine. No interactive neurochemical effects were observed in the dorsal striatum (pharmacological and genetic study) or in a preliminary study of the mPFC (genetic study only). On a progressive ratio task measuring motivational salience, the direction of the interactive effect between COMT genotype and THC differed between 2 independent cohorts and provided tentative leads that stress/arousal-dependent effects on COMT may have a confounding effect. My data provide evidence that COMT activity modulates the effect of THC on accumbal dopamine function, and suggest the mechanism through which this interaction is mediated differs between acute and lifelong reduction in COMT activity. Through the interactive effect on the dopaminergic system, the data provide a potential mechanism for the reported interaction between COMT and cannabis/THC in determining psychosis risk and cognitive impairments.

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Jacobs, Sarah. "Development of a COMT PCR multiplex to investigate resilience, anxiety and childhood trauma in a South African population". University of the Western Cape, 2020. http://hdl.handle.net/11394/7923.

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>Magister Scientiae - MSc
Anxiety, resilience and childhood trauma can be categorized as functional behavioural categories, with a wealth of research behind each. The research approach adopted for each, in most cases, is either from a genetic or neuropsychological standpoint, with few studies combining both to better understand all three functional behavioural categories as a multidimensional construct A number of candidate genes have been identified as markers for anxiety, resilience and childhood trauma, of which Catechol-methyl-transferase (COMT) and several respective single nucleotide polymorphisms (SNPs) are included. Although COMT SNPs have been linked to at least one of the functional categories, with a handful of haplotypes identified, to our knowledge no study has investigated the combination of SNPs selected for this study (rs6269, rs4818, rs4680, rs4633, rs737865, rs2075507) as a possible haplotype, specifically in a South African population. The use of SNaPshot for the genotyping of genes is an efficient and reliable means of identifying genotype frequencies and haplotypes in large sample groups, yet when selecting more than two SNPs of interest, the development of a multiplex assay is ideal. The first aim of the study was to design and optimize a multiplex assay to genotype several COMT SNPs. The primer design, multiplex optimization and SNaPshot conditions used showed good working parameters that can be utilized and further improved by optimization. Self-report measures are widely used to measure psychiatric disorders, such as anxiety, and has also been used for the measurement of resilience and childhood trauma. With each functional behavioural category well investigated in its respective domain, there is a need to investigate all three as a collective in a South African population due to the high rate of anxiety and childhood trauma exposure in communities. The second aim of the study was to investigate the prevalence of anxiety, resilience and childhood as functional behavioural categories in the full South African sample group; and the role of sex, through established self-report measures and respective normative data. Additionally, this carried over into investigating the correlation between anxiety, resilience and childhood trauma as a multidimensional construct in both the full South African sample and between sexes. There is a clear relationship which exists between all three functional behavioural categories, as they show a correlation in various dimensions independent of one another. Higher anxiety levels amongst females were reported, with no difference between sexes for resiliency. The empirical data collected from both COMT SNP and self-report measures for male and female where explored and reviewed against current literature for better understanding and insight into the association of COMT SNPs with anxiety, resilience and childhood trauma in a South African population. The results of this study to understand the complexity and association of all three functional behavioural categories as a multidimensional construct will be invaluable and may assist in the identification of possible risk factors which are essential for the promotion of better mental health in society.

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Lerner, Christian Daniel. "Strukturbasiertes Design, Synthese und in vitro Bewertung von Bisubstrat-Inhibitoren der Catechol-O-Methyltransferase (COMT) /". [S.l.] : [s.n.], 2003. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=15033.

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Korn, Clio. "Contributions of COMT and DAT to regulation of phasic dopamine release and reward-guided behaviour". Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:8772a01d-665d-454e-9e3c-bf734331a1c2.

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Fine temporal regulation of dopamine transmission is critical to its effects on behaviour. Dopamine can be cleared from the synapse either by recycling via the dopamine transporter (DAT) or by enzymatic degradation involving catechol-O-methyltransferase (COMT). DAT recycling predominates in striatum and contributes to dopaminergic regulation of reward-guided behaviour, while COMT degradation predominates in cortex and modulates executive functions. However, human functional imaging studies demonstrate interactive effects of DAT and COMT genotype, suggesting that the traditional division between DAT and COMT is not so clear-cut. Given the interdependence of mesolimbic and mesocortical circuitry and the presence of COMT in the striatum, it is possible that DAT and COMT interact to a greater extent than previously thought. We investigated the contributions of DAT and COMT to regulation of dopamine transmission and reward-guided behaviour by combining in vivo electrochemical recording, pharmacology, and behavioural testing in mice. Using fast scan cyclic voltammetry to record evoked dopamine release in anaesthetised animals, we found that systemic DAT blockade increased the size of dopamine transients in the nucleus accumbens (NAc) but not in the medial frontal cortex (MFC), demonstrating that DAT regulates phasic striatal dopamine release and confirming that DAT makes little contribution to regulation of cortical dopamine transmission. Unexpectedly, COMT inhibition did not affect evoked dopamine transients in either the NAc or the MFC. In agreement with these findings, systemic administration of a DAT blocker, but not of a COMT inhibitor, increased motivation to work for reward in a progressive ratio paradigm. COMT inhibition also had little effect on reinforcement learning (RL) strategies during reward-guided decision making. Intriguingly, however, we found that DAT blockade both decreased the influence of model-free RL and increased the influence of model-based RL on behaviour. Our study confirms that DAT regulates dopamine transmission in striatum but not in cortex and indicates that sub-second changes in dopamine transmission in both regions are largely insensitive to COMT. However, our behavioural data reveal the importance of striatal dopamine in multiple components of reward-guided behaviour, including both motivational aspects traditionally associated with striatum as well as cognitive aspects heretofore mainly associated with cortical function. Together, these findings emphasise that reward processing occurs across corticostriatal circuits and contribute to our understanding of how striatal dopamine transmission regulates reward-guided behaviours.

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Oliveira, Angélica Salatino de. "O polimorfismo Val158Met do gene COMT e TDAH : um estudo de suscetibilidade genética e farcogenética". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2011. http://hdl.handle.net/10183/139173.

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O transtorno de déficit de atenção e hiperatividade (TDAH) é uma doença psiquiátrica de etiologia complexa, muito comum em crianças e adolescentes. Caracteriza-se pelos sintomas de desatenção, hiperatividade e impulsividade, além de uma alta taxa de comorbidade com transtornos disruptivos do comportamento. Em relação a sua neurobiologia, uma hipótese atualmente aceita é de que crianças com TDAH apresentam um déficit funcional significativo do córtex pré-frontal, com um aparente desequilíbrio de catecolaminas. A enzima Catecol-O-metiltransferase (COMT) atua na degradação de catecolaminas na fenda sináptica e é responsável pela maior parte da degradação de dopamina no córtex pré-frontal. Dessa forma, esta enzima age diretamente no balanço dopaminérgico e noradrenérgico. O polimorfismo Val158Met do gene COMT ocasiona uma troca de aminoácidos, afetando sua termoestabilidade enzimática. Estudos indicam que esta variação enzimática da COMT tem um papel relevante na heterogeneidade fenotípica encontrada no TDAH, podendo estar envolvida no surgimento de transtornos disruptivos do comportamento. Em relação ao tratamento, o fármaco comumente prescrito é o metilfenidato. Este medicamento parece agir diretamente no aumento dos níveis de catecolaminas na fenda sináptica, através do bloqueio do transportador de dopamina e de noradrenalina. Devida a ação direta da COMT na degradação de catecolaminas e a importância do nível desses neurotransmissores na melhora da sintomatologia do TDAH, fazse também necessário o conhecimento sobre o possível efeito farmacogenético do gene no transtorno. Um total de 473 crianças foram genotipadas para o polimorfismo Val158Met. O diagnóstico de TDAH e suas comorbidades foi realizado através de três estágios, previamente descrito na literatura. Dentre esses pacientes, 251 satisfizeram os critérios de inclusão para participar do estudo farmacogenético. Variáveis que poderiam atuar como potenciais confundidores foram analisadas. As dosagens de metilfenidato foram aumentadas até não haver mais melhora clínica ou até existirem efeitos adversos significativos (doses acima de 0,3 mg/kg/dia). A medida dos sintomas foi baseada na Escala de Swanson, Nolan e 4 Pelham versão IV, e aplicada pelos psiquiatras (sem o conhecimento dos genótipos dos pacientes) antes do tratamento e no primeiro e terceiro mês de tratamento Pacientes com o genótipo Val/Val mostraram uma taxa 12% maior de transtornos disruptivos do comportamento quando comparados com indivíduos portadores do alelo Met (2 = 5,729, p = 0,017, OR = 1,62). De acordo com o teste farmacogenético, foi encontrado um efeito significante do tempo de tratamento (n = 112; F2,231 = 5,35, p = 0,005) e do gene COMT (F1,148 = 5,02, p = 0,027) na melhora clínica dos escores de oposição. Além disso, também foi vista uma interação significante entre a presença do alelo Met e o tempo de tratamento nos escores de oposição nesse período (F2,229 = 6,40, p = 0,002). Nossos resultados indicam que existe uma diferença significante na presença de transtorno disruptivo do comportamento em crianças com TDAH, de acordo com o genótipo do polimorfismo Val158Met. O genótipo Val/Val parece predizer a presença desse comportamento antissocial em crianças com TDAH. Além disso, nosso estudo farmacogenético mostrou um efeito prejudicial do genótipo Val/Val na melhora clínica dos sintomas de oposição em meninos com TDAH tratados com metilfenidato.
Attention-Deficit Hyperactivity Disorder (ADHD) is a common psychiatric condition that affects children and adolescents worldwide. This disorder is defined by symptoms of inattention and hyperactivity/impulsivity. Comorbidity with other disorders, such as Disruptive Behaviour Disorders (DBD) is very common. Regarding ADHD‟s neurobiology, there is a hypothesis that children with ADHD have prefrontal cortex (PFC) deficits with inadequate catecholamine transmission. The enzyme catechol-O-methyltransferase (COMT) degrades catecholamines and it has been suggested that it plays a key role in prefrontal cortical functioning. COMT accounts for most of the degradation of dopamine in the PFC. The Val158Met polymorphism is functional. It affects the thermostability of the protein. Several studies suggest that this variation in COMT has a relevant role in ADHD heterogeneity, and it can lead to emergence of DBD. Methylphenidate (MPH) is the most widely used drug to treat ADHD. The effect of MPH on catecholaminergic pathways results in an improvement of the PFC functioning by blockade of dopamine and norepinephrine transporters. Due to action of COMT in catecholaminergic balance, it is necessary to know about the pharmacogenetic effect of COMT in ADHD. A sample of 473 children with ADHD was genotyped for the Val158Met polymorphism. A consensus diagnosis of ADHD with or without comorbidity was achieved through a three-stage process, as previously described in the literature. Around these patients, 251 children with ADHD fulfilled inclusion criteria to participate in the pharmacogenetic study. Potential confounders were evaluated. Dosages of short-acting MPH were augmented until no further clinical improvement was detected or until there were significant adverse events (MPH dose always > 0.3 mg/kg/day). The outcome measure was the parent-rated oppositional subscale of the Swanson, Nolan and Pelham Scale – version IV. The scale was applied by child psychiatrists blinded to genotype at baseline and in the first and third months. Patients homozygous for Val allele showed a higher frequency of DBD (+ 12%) than Met allele carriers (2 = 5.729, p = 0.017, OR = 1.62). We detected 6 significant improvement in SNAP-IV oppositional scores from baseline to the first and three months of treatment (n = 112; F2,231 = 5.35, p = 0.005). A significant effect of the presence of Met allele during three months of treatment (F1,148 = 5.02, p = 0.027), and a significant interaction between the Met allele and treatment over time for the SNAP-IV oppositional scores during this period of treatment (F2,229 = 6.40, p = 0.002) were both observed. Therefore, our results indicate that there is a significant difference in the presence of disruptive behavior disorders in children with ADHD according to Val158Met genotype. This antisocial behavior in children with ADHD seems to be predicted by Val/Val genotype in COMT gene. Moreover, pharmacogenetic results suggest an effect of the COMT genotype on the trajectory of ODD symptoms improvement with MPH treatment in boys with ADHD.

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Masjost, Birgit. "Structure-based design, synthesis, and in vitro evaluation of bisubstrate inhibitors for catechol o-methyltransferase (COMT) /". [S.l.] : [s.n.], 2000. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=13719.

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Choudhry, Zia Ulhaq. "Catechol-O-Methyltransferase (COMT) Val 108158 Met polymorphism and ADHD : pharmaco-behavioural genetic and neurocognitive study". Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112389.

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The catechol-O-methyltransferase (COMT) gene is the predominant means of dopamine deactivation within the prefrontal cortex (PFC), a brain locus implicated in Attention deficit/hyperactivity disorder (ADHD). Dopamine dysregulation is a significant contributor to the pathophysiology of ADHD and Methylphenidate (MPH), an effective treatment for ADHD, and acts at least in part, through modulation of dopamine levels in the PFC. Thus, we tested the hypothesis that the Catechol-O-Methyltransferase (COMT) Val108/158 Met polymorphism modulates behavioral dimensions relevant for ADHD and/or response of these behavioral dimensions to MPH and/or neuropsychological functions considered relevant for ADHD. No genotype or genotype by treatment interaction effects were observed for behavioral response to MPH. No genotype effects were observed using the family-based approach. Marginal genotype effects were observed between the Met/Met genotype and some but not all aspects of executive functioning. Overall, these results do not support the implication of the COMT Val108/158 Met polymorphism in ADHD, ADHD relevant behaviours or response to methylphenidate, but weakly implicate COMT gene in some aspects of executive functions in children with ADHD. Given that gene effects on behaviours are likely to be very small, a much large sample would be needed in order to establish these results, both negative and positive, with better confidence.

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García, García Manuel Antonio. "The role of COMT, DAT and DRD2 polymorphisms on brain mechanisms of involuntary attention and cognitive control". Doctoral thesis, Universitat de Barcelona, 2009. http://hdl.handle.net/10803/2722.

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Our genetic background plays a role in the way we face environmental changes and adapt our behavior adequately to the requirements of everyday life. The present research focuses on the role of three genes related to dopamine (DA) transmission on relevant cognitive processes, such as shifting attention when required by the environmental demands or processing of unexpected but potentially relevant events. Prefrontal cortex (PFC) and striatum dopamine activity seem to play different roles in attentional processing and interact to regulate stability and flexible update of context information. Therefore, we studied the action of genes regulating PFC dopamine action (i.e., Catechol-O-Methyltransferase; COMT), reuptake of dopamine diffused on extrasynaptic striatal space (i.e., Dopamine Transporter; DAT) and the concentration of D2-type dopamine receptors (i.e., dopamine D2 receptors; DRD2).

The results of these studies provide evidence for a relevant role of COMT, DAT1 and DRD2 genes in cognitive processes, which helps to understand cognitive disruption associated to dopamine dysregulation in psychiatric disorders.
Els nostres gens juguen un rol important en la manera que enfrontem els canvis de l'ambient i adaptem la nostre conducta adequadament. El present treball de recerca se centra en el paper de tres gens relacionats amb la dopamina (DA) sobre processos cognitius, com el canvi de l'atenció quan és requerit per les demandes ambientals o el processament d'esdeveniments inesperats però potencialment rellevants. L'activitat dopaminèrgica al còrtex prefrontal (PFC) i a l'estriat semblen jugar papers diferents en el processament atencional i interaccionen per a regular l'estabilitat i flexibilitat de l'actualització de la informació contextual. Per això, vam estudiar l'acció de gens que regulaven l'acció de la dopamina del PFC (i.e. Catechol-O-Methyltransferase; COMT), la resposta de dopamina difosa en l'espai extrasinàptic estriatal (i.e. Transportador de Dopamina; DAT) i la concentració de receptors de dopamina de tipus D2 (i.e. receptors D2 de dopamina; DRD2).

Els participants amb diversos al·lels dels gens estudiats van realitzar dues versions diferents d'un paradigma de distracció auditiu visual, en el qual se'ls demanava que ignoressin tons estàndards freqüents i sons ambientals nous rars que precedien els objectius pertinents de la tasca. En dos estudis, vam manipular l'efecte d'un context emocional sobre el processament d'esdeveniments nous inesperats, donada la potencial rellevància d'un esdeveniment nou durant una situació d'amenaça en la qual pot ser nociu. En tres estudis, els participants amb al·lels diferents o combinacions d'al·lels van realitzar un paradigma de commutació de tasca, en el qual l'actualització d'informació sensorial i de tasca es podria dissociar. Al llarg dels sis estudis, se van emprar mesures conductuals i electrofisiològiques enregistrades al cuir cabellut, com els anàlisis de l'electroencefalograma (EEG) al domini del temps promitjant els potencials cerebrals relacionats a esdeveniments (ERP), i l'activitat oscil·latòria cerebral al domini temps- freqüència.

Tres estudis van mostrar el paper del gen del DAT en el control cognitiu de l'atenció, suggerint així la pertinència de la DA estriatal en la flexibilitat cognitiva. Els nostres resultats suggereixen un processament independent del context dels canvis sensorials per la reconfiguració del set de la tasca en individus amb l'al·lel de 9 repeticions de DAT (9R+) relacionats amb una major disponibilitat de dopamina estriatal. Tanmateix, aquests individus van mostrar una detecció primerenca de la rellevància per la tasca dels canvis sensorials. El gen del DAT regulava la modulació del processament de la novetat per un context emocional. Els individus 9R+ van mostrar una resposta cerebral més gran als estimuls novedosos.

Dos estudis van mostrar el paper de la interacció dels gens de la COMT i del DRD2 sobre processos atencionals. S'ha suggerit que els individus amb l'al·lel de COMT Val i l'al·lel de DRD2 A1 (A1+) i COMT Met sense l'al·lel de DRD2 A1 (A1-) mostren una interacció equilibrada de dopamina prefrontal i estriatal. Aquests grups van mostrar distracció conductual, mentre que els individus ValA1- i els individus MetA1+ no van ser distrets per sons nous en un paradigma de distracció visual auditiu. Els grups, tanmateix, no-distrets resultaven processar esdeveniments nous a través de la restauracio d'activitat neuronal a 40 Hz. A més, aquells amb una interacció equilibrada semblaven tornar a configurar la informació de la tasca quan era necessari, mentre que aquells amb dopamina PFC o estriatal extremes tornarien a configurar el set de la tasca després de cada canvi sensorial.

Els resultats dels estudis de la tesi proporcionen una evidència del paper rellevant dels gens de la COMT, el DAT1 i el DRD2 en processos cognitius, i ajuden a entendre els dèficits cognitius associats a la disregulació de la dopamina en trastorns psiquiàtrics.

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Wendler, Franziska Verfasser], i Stefan [Akademischer Betreuer] [Pollmann. "Genetic influences on long-term memory control : COMT and retrieval-induced forgetting / Franziska Wendler. Betreuer: Stefan Pollmann". Magdeburg : Universitätsbibliothek, 2014. http://d-nb.info/1054638551/34.

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Capitão, Luísa Maria Sousa Ribeiro. "Estudo dos polimorfismos CYP1B1 VAL432 LEU, MTHFR Ala225VAL e COMT VAL158 Met como factores de risco de cancro da mama em mulheres da Beira Interior". Master's thesis, Faculdade de Medicina da Universidade do Porto, 2007. http://hdl.handle.net/10216/22131.

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Capitão, Luísa Maria Sousa Ribeiro. "Estudo dos polimorfismos CYP1B1 VAL432 LEU, MTHFR Ala225VAL e COMT VAL158 Met como factores de risco de cancro da mama em mulheres da Beira Interior". Dissertação, Faculdade de Medicina da Universidade do Porto, 2007. http://hdl.handle.net/10216/22131.

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Cuyàs, Navarro Elisabet. "Pharmacogenetic mechanisms (COMT and hSERT) modulating deleterious effects of MDMA and cannabis on cognitive performance in drug users". Doctoral thesis, Universitat Autònoma de Barcelona, 2011. http://hdl.handle.net/10803/48529.

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La neurotransmissió dopaminèrgica i serotonèrgica al còrtex preforntal i a les regions del sistema límbic són un dels principals substrats cerebrals de les funcions executives (implicades en l’organització i el control) i la regulació emocinal. Tant la MDMA com el cannabis alteren la funcionalitat d’aquests sistemes de neurotransmissió. Certs polimorfismes funcionals de la catecol-Ometiltransferasa (COMT) i del transportador de serotonina (hSERT) s’han associat a diferències individuals en el funcionament cognitiu. La interacció entre ambdós gens juntament amb factors ambientals poden explicar la major o menor susceptibilitat dels consumidors a els efectes deleteris de les substàncies psicoactives en les arees. L’objectiu és investigar la interacció de diversos polimorfismes relacionats amb els sistemes serotonergic i amb el rendiment d’una població de consumidors de MDMA i cannabis en la realització de diverses tasques neuropsicològiques (memòria i funcions executives pricipalment).
The serotonergic and dopaminegic neurotransmission at the prefrontal-cortex and the areas related to the limbic system, are one of the main substrates for the executive functions (involved in different tasks such as organization and control). Some drugs such as MDMA or cannabis are known to alter these neurotransmission systems. Some functional polymorphisms within the catechol-O-methyltransferase (COMT) and the serotonin transporter gene (hSERT) have been associated to interindividual differences in the cognitive performance. The interaction between both genes and ambient factors can explain to some extent, the different susceptibility of drug users to the deleterious effects of these psychoactive substances. The main objective is to study the relationship between several polymorphisms within the serotonergic and dopaminergic neurotransmission systems and the cognitive performance of a sample of MDMA and cannabis users in several neuropsychological tasks (mainly related to memory and executive functions).

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Lewandowski, Kathryn Eve. "The role of COMT in schizophrenic-like cognitive impairment and social functioning in children with 22q11 deletion syndrome". Greensboro, N.C. : University of North Carolina at Greensboro, 2007. http://libres.uncg.edu/edocs/etd/1480Lewandowski/umi-uncg-1480.pdf.

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Thesis (Ph. D.)--University of North Carolina at Greensboro, 2007.
Title from PDF t.p. (viewed Feb. 29, 2008). Directed by Thomas R. Kwapil; submitted to the Dept. of Psychology. Includes bibliographical references (p. 79-111).

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Herrmann, Lennard Manes Richard [Verfasser], Siegfried Martin [Gutachter] Muhlack i Ludgera Martina [Gutachter] Ossege-Pohle. "COMT-Inhibitoren in der Parkinson-Therapie / Lennard Manes Richard Herrmann. Gutachter: Siegfried Martin Muhlack ; Ludgera Martina Ossege-Pohle". Bochum : Ruhr-Universität Bochum, 2016. http://d-nb.info/1102524948/34.

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Schuh, Artur Francisco Schumacher. "Farmacogenética da levodopa na doença de Parkinson : estudo de polimorfismos nos genes da COMT, MAO-B e DAT". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2010. http://hdl.handle.net/10183/39639.

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A doença de Parkinson é a segunda enfermidade neurodegenerativa mais frequente e acomete entre 1 a 2% das pessoas acima de 65 anos. Com a expectativa de envelhecimento da população, espera-se um aumento proporcional da prevalência desta doença, o que justifica uma preocupação crescente com o manejo dessa condição. A levodopa é fundamental para o manejo farmacológico desses pacientes, uma vez que é possível um controle quase ótimo dos sintomas, pelo menos nos primeiros anos de tratamento. Entretanto, em cinco anos, cerca de metade dos pacientes apresentarão complicações pelo uso crônico desta medicação, o que determinará piora da qualidade de vida e um desafio ao médico, no sentido de controlar esses fenômenos. As principais complicações crônicas são as flutuações da resposta motora, as discinesias e as alucinações. Este trabalho tem a proposta de investigar a gênese dessas alterações em sua relação com variações genéticas específicas. Foram selecionados polimorfismos em genes com plausibilidade biológica, por estarem envolvidos na farmacocinética e farmacodinâmica da levodopa. São eles: Val158Met da COMT (catecol-orto-metiltransferase), íntron 13 da MAO-B (monoamina oxidase B), VNTR (“variable number tandem repeat”) de 40pb da região 3'UTR (“untranslated region”) do DAT (transportador de dopamina) e -839C>T da região promotora 5' do DAT. A COMT e a MAO-B são as duas rotas enzimáticas de degradação da dopamina e o DAT é um transportador présináptico de dopamina. Foram selecionados pacientes com doença de Parkinson idiopática em acompanhamento no Serviço de Neurologia do HCPA com idade de início dos sintomas após os 45 anos e que estavam em uso de levodopa há pelo menos dois anos. Esses pacientes foram submetidos a um protocolo de avaliação clínica, com obtenção de informações relevantes para a determinação da presença das complicações, aplicação de escalas padronizadas e coleta de sangue (ver anexos para o protocolo e as escalas). Após, o material biológico foi submetido à extração de DNA e os polimorfismos determinados por análise de fragmentos de enzima de restrição, no Departamento de Genética da UFRGS. Entre os polimorfismos da COMT e da MAO-B não se observou diferença para a presença ou ausência de flutuação da resposta motora, discinesia e alucinação. Entretanto, pacientes com genótipo lento da COMT (MetMet) apresentaram menos complicações da terapia (desfecho aferido pela parte IV da UPDRS, “Unified Parkinson Disease Rating Scale”, que fornece um escore cuja pontuação baixa representa menos complicações da terapia). Fazendo análise dos subítens da escala, observou-se que esse efeito se deveu à menor presença de flutuação motora. Observamos ainda que os pacientes portadores do genótipo MetMet apresentaram idade de início da doença de Parkinson menor quando comparados aos portadores dos genótipos de atividade rápida (ValMet e ValVal). A diferença aproximada foi de 4 anos, com um p=0,03. Seguindo o estudo da influência genética sobre a idade de início, observou-se que homens hemizigotos para o alelo G da MAO-B apresentavam idade de início precoce em relação aos portadores do alelo A, com diferença aproximada de 5 anos e p=0,03. Tomados em conjunto os polimorfismos da COMT e da MAO-B, o efeito do genótipo lento MetMet da COMT sobre a idade de início foi potencializado naqueles com alelo A da MAO-B (homens hemizigotos A e mulheres homozigotas AA), com diferença aproximada de oito anos e p=0,001. Em relação ao gene do DAT, observou-se que a presença do alelo T do polimorfismo da região promotora está associada à maior frequencia de alucinação visual, com OR (“odds ratio”, ou razão de chances) de 5,17 e IC (intervalo de confiança) de 95% de 1,45-18,41 com p=0,01. Ademais, encontrou-se um achado a ser melhor explorado: pacientes portadores do alelo de 9 repetições do VNTR de 40pb necessitavam de maior dose para o controle dos sintomas parkinsonianos, com uma diferença aproximada de 100mg com p=0,042. Há na literatura estudos de associação desses polimorfismos com a presença da doença de Parkinson, entretanto, poucos avaliaram o efeito dessas variantes polimórficas sobre a resposta ao uso de levodopa e sobre outros fatores clínicos. Os resultados desta dissertação trazem informações importantes para o melhor entendimento da variabilidade da resposta farmacológica e sobre a fisiopatologia da doença de Parkinson.

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Alazizi, Adnan. "Molecular Cloning, Expression, purification and Characterization of the Zebrafish Catechol-O-methyltransferases". University of Toledo Health Science Campus / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=mco1303391786.

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Giannunzio, Valeria. "Different Types of Decision Making Impairments in Anorexia Nervosa". Doctoral thesis, Università degli studi di Padova, 2017. http://hdl.handle.net/11577/3424927.

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Research on neurocognitive aspects in Anorexia Nervosa (AN) has outlined a cognitive profile characterized by deficiency in the ability to set-shifting (cognitive flexibility) and weak central coherence. A smaller agreement emerges in relation to the compromission of decisional profiles frequently observed in patients with AN since both the complexity of the pathology and the executive function itself make it unclear the nature of these alterations and its relationships with specific or independent clinical and enviornmental variables. The aim of this study was: to investigate different types of decision-making (DM) ability, veridical and adaptive, in a sample of patients with AN using the Iowa Gambling Task and the Cognitive Bias Task; to analyze test performance using a specific cognitive model for the Iowa Gambling Task (Expectancy Valence Learning Model), and to study the relationship with clinical features, focusing on their relationship with neuropsychological profiles and clinical variables; to explore the neural correlations of the two tasks with functional connectivity; to observe the the impact of the genetic profile on different types of DM. Materials and Methods: The sample, consisting of 310 female subjects with AN lifetime and 301 female subjects without diagnosis of lifetime eating disorders, was tested in relation to DM abilities through the Iowa Gambling Task and cognitive Bias Task. All of the participants completed a baseline assessment including the Structured Clinical Interview (SCID) for the DSM-IV, section for eating disorders, and neuropsychological tests including the Wisconsin Card Sorting Test, and Trail Making Test for assessing abilities of abstraction and cognitive flexibility; 10 "and 30" interference memory test for evaluation of working memory, Stop Signal Task for evaluation of inibitory control. The Expectancy Valence Model (EVM) was used to analyze the results obtained in IGT. A genotyping was performed to evaluate the impact of the major polymorphisms implicated in decision-making (158 Val → Met) of the COMT gene and single nucleotide A / G polymorphism (SNP rs25531) of the serotonin carrier gene 5 - HTTLPR. In a smaller subgroup of 35 AN and 34 Healthy control seed based resting state Functional connectivity was explored. Compared to the group of healthy subjects, the decision-making profile of patients suffering from AN was worse in both Iowa Gambling Task (IGT), which evaluates veridical DM, and Cognitive Bias Task (Cbias), which evaluates adaptive DM, regardless of the diagnostic subtype (restrictive vs. binging/purging), psychopathology severity, scholarity, manual 3 dominance or outcome specific treatment. However in IGT the affective decision-making seems to be independent of IMC, conversely in Cbias the adaptive decisional profile was influenced by underweight. Both types of decision-making in patients were not affected by neurocognitive or clinical variables considered. The unfavorable geotype in AN resulted the homozygous for the met allele of the Comt gene and for the short variant of the serotonin transporter gene. The resting functional connectivity explored on the seeds of interest (executive network, orbitofrontal cortex, accumbens and amygdala) in a subgroup of patients and controls showed significantly different patterns of correlation with the scores of IGt and Cbias. In addition, different resting neural patterns appear to be involved in the two different tasks considered. Only in the AN group a positive correlation between the scores on IGT and the activity of the amygdala resulted. In AN group an higher coactivation within the executive, accumbens and orbitofrontal networks was linked to higher context-independency decisional style assessed with CBias, whereas for the executive network the opposite was true for healthy women. In summary our results confirm an impairment of different types of decision making in AN and highlitght the importance of assessing decisional processes with different specific tasks in clinical sample. In particular different maladaptative strategies are associated with ineffective decisional profiles in AN, consisting in a “myopia for the future” and “anxiety inhibition” in veridical situations and in a difficulty to update/review one’s own mindset according to new environmental stimuli (context indipendent reasoning strategies) in adaptive decisional framework. The severity of malnurishment seems to influence adaptive decisional style conferring a bias toward a context indipent reasoning, suggesting the need of metacognitive approach to help patients to be more aware of their tendency to automatically use selection bias in DM contexts. Genetic polimorphysms may in part account for the impaired decision making observed in AN patients, with a negative impact of met Comt allele and the short variant of 5HTTLPR polymorphism. Functional connectivity suggests the presence of different dysfunctional decision making networks in AN patients in the two decisional framework, confirming the importance of emotion and anxiety on decisional performance in AN. Since the cross sectional design of our study, further and longitudinal studies with recovered and at risk subjects are necessary to confirm our results.
La ricerca sugli aspetti neurocognitivi nell’anoressia nervosa (AN) ha delineato un profilo cognitivo caratterizzato da deficit nell’abilità di set-shifting (flessibilità cognitiva) e da debole coerenza centrale. Un minor accordo emerge in relazione alla compromissione dei profili decisionali frequentemente osservata nelle pazienti con AN dal momento che la complessità della patologia e della funzione esecutiva stessa rendono poco chiara la natura di tali alterazioni e le relazioni con aspetti clinici specifici della malattia o indipendenti da essa. Il nostro studio si propone di valutare la capacità decisionale di un campione di pazienti affette da AN utilizzando l'Iowa Gambling Task, e il Cognitive Bias Task, di analizzare le performance al test utilizzando un modello cognitivo specifico per l’Iowa Gambling Task (Expectancy Valence model), e di studiare le relazioni tra i risultati ottenuti e le caratteristiche cliniche delle pazienti focalizzandoci nella loro relazione con aspetti caratteristici del profilo neuropsicologico e della presentazione della malattia come la precoce età di esordio. Approfondire i correlati anatomici, di connettività strutturale e funzionale delle perfomance ai due task e l’impatto dell’assetto genetico. Il campione, costituito da 310 soggetti di sesso femminile con diagnosi lifetime di AN e 301 soggetti di sesso femminile senza diagnosi di sturbo del comportamento alimentare è stato testato in relazione alle abilità decisionali attraverso l’Iowa Gambling Task. Tutti i soggetti, previo consenso informato, hanno completato una valutazione sia clinica che semistrutturata mediante la somministrazione dell’Intervista Clinica Strutturata (SCID) per il DSM-IV, sezione per i disturbi del comportamento alimentare. E’ stata somministrata una batteria di valutazione neuropsicologica includente: the WCST Wisconsin Card Sorting Test and Trail Making Tet sper la valutazione dell’abilità di astrazione e della flessibilità cognitiva; test di Memoria con interferenza a 10" e 30" per la valutazione della memoria di lavoro; SSRT per la valutazione del controllo inibitorio. E' stato utilizzato inoltre uno specifico modello cognitivo (Expectancy Valence model) al fine di analizzare i risultati ottenuti all'IGT. È stata effettuata una genotipizzazione per valutare l’impatto dei principali polimorfismi ritenuti implicati nelle performance decisionali (158 Val → Met del gene COMT, la variante corta e il polimorfismo a singolo nucleotide A/G (SNP rs25531) del gene del trasportatore della serotonina 5-HTTLPR. Un sottogruppo di 35 soggetti affetti da AN e 34 controlli sani infine si è sottoposto a risonanza magnetica funzionale a riposo. E’ stata condotta un’analisi della connettività funzionale basata su “seed” in specifiche regioni di interesse (network esecutivo, corteccia orbitofrontale, network dell’accumbens ed amigdala). I risultati confermano la presenza di un peggior profilo decisionale all’ IGT nelle pazienti affette da Anoressia nervosa indipendentemente dall’età del soggetto, tuttavia il deficit decisionale sembra essere indipendente dall’IMC nell IGT ma influenzato dal sotto peso nel Cbias. Entrambi i diversi tipi di decision making nelle pazienti non risentono dall’assetto neurocognitivo o dalle variabili cliniche prese in esame. L’assetto genetico sfavorevole nelle pazienti sembrerebbe essere l’omozigosi per l’allele met del gene Comt e per la variante S del trasportatore della serotonina. Rispetto al gruppo di soggetti sani, il profilo decisionale delle pazienti affette da Anoressia Nervosa è risultato peggiore sia allo Iowa Gambling Task (IGT), che valuta le abilità deciosionali di tipo veridico, che al Cognitive Bias Task (Cbias), che valuta le abilità decisionali di tipo adattativo, indipendentemente dal sottotipo diagnostico (restrittivo vs bulumico purgativo), psicopatologia, scolarità o dominanza manuale. La connettività funzionale a riposo esplorata sui seed di interesse (network esecutivo, corteccia orbitofrontale, accumbens e amigdala ) in un sottogruppo di pazienti e controlli ha mostrato nei due gruppi pattern significativamente diversi di correlazione con i punteggi all’IGt e al Cbias. Inoltre pattern neurali differenti a riposo sembrano essere coinvolti nei due diversi task considerati. È stata identificata solo nel gruppo di AN una correlazione positiva tra i punteggi all’IGT e l’attività dell’amigdala. Nelle pazienti una maggior coattivazione all’interno del network esecutivo , orbitofrontale e dell’accumbens è legata a performance decisionali maggiormente indipendenti dal contesto al Cbias, mentre per il network esecutivo accade il contrario nei soggetti sani.

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Miguita, Karen. "Estudo de associação de genes candidatos no transtorno obsessivo-compulsivo: investigação dos loci SLC6A4, HTR1B, HTR2A, SLC6A3, COMT e SLC6A2". Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/5/5142/tde-23102007-110042/.

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O Transtorno obsessivo-compulsivo (TOC) é um transtorno psiquiátrico comum e heterogêneo caracterizado por obsessões (pensamentos, imagens ou impulsos intrusivos e recorrentes) e compulsões (comportamentos ou atos mentais repetitivos realizados para aliviar as obsessões). O TOC tem uma prevalência de 2 a 3% na população geral e apresenta distribuição aproximadamente igual entre os sexos, porém os homens tendem a apresentar os sintomas obsessivo-compulsivos mais precocemente quando comparado com as mulheres. Os estudos de genética epidemiológica têm demonstrado que o fator genético é um importante componente na etiologia do TOC. O principal objetivo desta dissertação foi investigar a influência de alguns genes candidatos na susceptibilidade para o TOC (estudo de genes candidatos) e também qual a influência destes mesmos genes na resposta terapêutica à clomipramina (estudo de farmacogenética). Realizamos o estudo de genes candidatos num total de 215 pacientes e 872 controles. Os loci investigados foram: SLC6A4, HTR1B, HTR2A, SLC6A3, COMT e SLC6A2. Os mesmos polimorfismos foram investigados em uma sub-amostra de 41 pacientes tratados com clomipramina e analisados de acordo com a resposta terapêutica. Foram classificados como respondedores ao tratamento, os pacientes que tiveram uma redução de 40% ou mais na escala YBOCS. Assim, 27 pacientes foram considerados respondedores e 14 nãorespondedores. Diferenças genotípicas e alélicas foram observadas em alguns resultados nos pacientes e controles. Entretanto, nenhuma associação foi observada nas análises para resposta à clomipramina. Os resultados sugerem que alguns polimorfismos estudados podem estar relacionados ao aumento do risco para o TOC, porém, nenhum polimorfismo foi associado à resposta terapêutica à clomipramina.
Obsessive-compulsive disorder (OCD) is a common and heterogeneous psychiatric disorder characterized by obsessions (intrusive and recurrent thoughts, images or impulses) and compulsions (repetitive behaviors or mental acts performed to relive obsessions). OCD prevalence range from 2 to 3% in general population and has approximately equal sex distributions, however men tend to have an earlier age at onset of obsessive-compulsive symptoms comparing to women. Epidemiologic studies have demonstrated that genetic factor is an important component in the etiology of OCD. The aim of this study was to investigate participation of some candidate genes in the susceptibility to OCD and also their effects on clomipramine treatment. We performed a candidate gene study in a total of 215 OCD patients and 865 controls. The loci investigated were: SLC6A4, HTR1B, HTR2A, SLC6A3, COMT and SLC6A2. The same polymorphisms were investigated in a sub-sample of 41 patients treated with clomipramine, and analyzed according to therapeutic response. There were considered good responders to the drug those patients who presented a reduction of 40% or more in Y-BOCS scale. According to this, 27 patients were good responders and 14 poor responders. Genotypic and allelic differences were observed in some results for patients and controls. However, no association was observed in the analyses for clomipramine response. Our results suggest that some polymorphisms investigated may be related to the increase of risk to develop OCD, but they are not associated to therapeutic response to clomipramine.

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Wortmann, Viola [Verfasser], i Volker [Akademischer Betreuer] Arolt. "Hippokampale Volumenveränderung und COMT-Val-108/158-Met-Polymorphismus bei Patienten mit akuter unipolarer Depression / Viola Wortmann. Betreuer: Volker Arolt". Münster : Universitäts- und Landesbibliothek der Westfälischen Wilhelms-Universität, 2011. http://d-nb.info/1027017762/34.

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Nüsser, Corinna. "Neuronale Korrelate von Delay Discounting". Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2009. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-23427.

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Delay Discounting im Sinne eines Abwertens zukünftiger Belohnungen ist ein weit verbreitetes Phänomen. Es zeigt sich z. B. in persönlichen Angelegenheiten, wie der Entscheidung für den kurzfristigen Genuss von Süßigkeiten und gegen die langfristigen, durchaus größeren Vorteile einer schlanken Figur. Auch internationale wirtschaftliche und politische Diskussionen zum Klimaschutz oder der Finanzkrise werden von der Präferenz für sofortige, kleinere Belohnungen über verzögerte, größere Belohnungen getrieben. In der Psychologie wird Delay Discounting als Maß für Impulsivität bzw. Selbstkontrolle mit dem Auftreten von Aufmerksamkeitsdefizit-Hyperaktivitäts-Syndromen und von Abhängigkeitserkrankungen in Verbindung gebracht. Bezüglich der neuronalen Grundlagen von Delay Discouting ist mithilfe von sogenannten Intertemporal Choice Tasks bereits herausgefunden worden, dass die Entscheidung für eine sofortige Belohnung stärkere neuronale Aktivierung in belohnungsspezifischen Gehirnregionen evoziert als die Entscheidung für eine verzögerte Belohnung. Außerdem wurden sowohl theoretisch wie auch empirisch ein impulsives und ein reflektives System als Grundlage des Delay Discounting beschrieben, deren Existenz jedoch von manchen Wissenschaftlern angezweifelt wird. Ebenso wird angezweifelt, ob Delay Discounting unabhängig vom Einsatz von Intertemporal Choice Tasks und der damit verbundenen Entscheidung zwischen zwei Alternativen überhaupt besteht. Da die neuronalen Grundlagen des Delay Discounting und des impulsiven und reflektiven Systems bisher nicht unabhängig von einer Entscheidungsaufgabe erfasst wurden, konnten diese Zweifel nicht ausgeräumt werden. Ebenso ist zurzeit unbekannt, ob sich die neuronalen Korrelate des Delay Discounting bei Personen mit unterschiedlichen Persönlichkeitseigenschaften, bei Männern und Frauen, bei Rauchern und Nichtrauchern und in Abhängigkeit von verschiedenen Genvarianten unterscheiden. Um diese Lücke zu schließen, ist im Rahmen der vorliegenden Arbeit ein neuartiges Delay Discounting Paradigma zum Einsatz im Magnetresonanztomographen entwickelt worden. Dieses Paradigma ähnelt einem Monetary Incentive Delay Task und ermöglicht es, neuronale Aktivierung bei der Antizipation und bei dem Erhalt einer einzelnen Belohnung zu einem Zeitpunkt zu erfassen. Außerdem kann nach der Antizipation einer Belohnung, die sich durch eine bestimmte Höhe (0,05 €, 0,50 €, 1,00 €) und eine bestimmte Auszahlungsverzögerung (0 Tage, 10 Tage, 100 Tage) auszeichnet, in einer einfachen visuellen Diskriminationsaufgabe eine Reaktionszeit erfasst werden, die als behaviorales Maß für die inzentive Motivation fungiert. Zusammen mit einer Erfassung verschiedener Persönlichkeitseigenschaften und einer Genotypisierung für den COMT Val 158 Met Polymorphismus, den DRD2 Taq 1 A Polymorphismus und den DAT 1 Polymorphismus ist das Delay Discounting Paradigma an insgesamt 90 Probanden im Magnetresonanztomographen eingesetzt worden, so dass 84 auswertbare Datensätze gewonnen werden konnten. Diese 84 Datensätze stammten insgesamt von 42 Frauen und 42 Männern bzw. von 43 strikten Nichtrauchern, 38 starken Rauchern und drei Gelegenheitsrauchern. Anhand der Auswertung der Gesamtstichprobe konnte bestätigt werden, dass das Delay Discounting Paradigma belohnungs- und verzögerungsspezifisch unterschiedliche Reaktionszeiten und unterschiedliche neuronale Aktivierung hervorruft. In belohnungsverarbeitenden Gehirnregionen wie dem ventralen Striatum zeigte sich sowohl stärkere Aktivierung für größere Belohnungen als auch für Belohnungen, die früher ausgezahlt wurden. Damit steht fest, dass Delay Discounting unabhängig von der Entscheidung zwischen zwei Alternativen auftritt. Außerdem konnte erstmalig ein Interaktionseffekt zwischen Belohnungshöhe und Belohnungsverzögerung aufgedeckt werden: Es zeigte sich eine Abnahme der Differenzen in der neuronalen Aktivierung zwischen größter und kleinster Belohnung über die Zeit, was auf eine Indifferenz gegenüber der Höhe verzögerter Belohnung hindeutet. Ein Einfluss der Belohnungsverzögerung wurde allerdings nur beim Erhalt von Belohnungen messbar, bei der Antizipation von Belohnungen zeigte sich kein Delay Discounting Effekt. Bezüglich der Kontroverse zur Existenz eines impulsiven und reflektiven Systems konnten Ergebnisse gewonnen werden, die beide Positionen integrieren. So wurde zwar die Beteiligung von zwei distinkten neuronalen Systemen beim Abwerten zukünftiger Belohnungen bestätigt, allerdings zeigte sich auch, dass beide Systeme – in einem unterschiedlichen Ausmaß – verzögerte Belohnungen abwerten. Trotzdem wird von den vorliegenden Ergebnissen die Annahme, dass sich aus der Interaktion von impulsivem und reflektivem System impulsives und selbstkontrolliertes Verhalten ergeben kann, gestützt. Im Hinblick auf die interindividuellen Unterschiede, die in der vorliegenden Arbeit aufgedeckt werden sollten, haben sich vor allem Zusammenhänge zwischen dem subjektiv berichteten allgemeinen Stress der Versuchspersonen (operationalisiert über das Selbststeuerungsinventar) und der neuronalen Aktivität von Gehirnregionen, die dem impulsiven und reflektiven System zugeordnet werden, gezeigt. So ist bei niedrigem Stress das impulsive System signifikant weniger aktiviert als das reflektive System, während sich bei hohem Stress dieser Zusammenhang umkehrt. Die relative Hyperaktivierung des impulsiven Systems bei Stress könnte erklären, warum unter Stress vermehrt Rückfälle bei abhängigkeitserkrankten Probanden beobachtet werden. Außerdem ging starkes neuronales Delay Discounting in medial präfrontalen Gehirnregionen mit hohem Stress, ebenso wie mit hoher nichtplanender Impulsivität (gemessen anhand der Barratt Impulsivitätsskala) und mit geringer Selbstkontrolle (gemäß des Selbststeuerungsinventars) einher. Dieses Ergebnis belegt unter anderem, dass das neu entwickelte Delay Discounting Paradigma neuronale Prozesse abbildet, die mit Impulsivität und Selbstkontrolle in Verbindung stehen. Darüber hinaus konnte kongruent mit entsprechenden Vorbefunden ein Einfluss des COMT Val 158 Met Polymorphismus auf das neuronale Delay Discounting im ventralen Striatum und erstmalig ein Zusammenhang zwischen dem DRD2 Taq 1 A A1-Allel und neuronalem Delay Discounting im posterioren Cingulum aufgedeckt werden. Damit ist die Bedeutung des Neurotransmitters Dopamin, der durch die untersuchten Polymorphismen beeinflusst wird, für die neuronalen Grundlagen des Delay Discounting bestätigt worden. Zusammengenommen deuten sowohl die beschriebenen Befunde als auch die sonstigen Ergebnisse der Arbeit darauf hin, dass sich neuronales Delay Discounting interindividuell unterscheidet. Im Hinblick auf Pathologien, die mit diesem Phänomen in Verbindung stehen, sollte daher weitere Forschung zu interindividuellen Unterschieden und zu spezifischen Behandlungsmethoden erfolgen.

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Fasolo, Juliana Maria de Mello Andrade. "Aplicação de CLAE-DAD-EM e CG-EM na caracterização de Blechnum sp. e abordagens in vitro e in silico para a avaliar o perfil multifuncional do ácido rosmarínico em alvos relacionados à neurodegeneração e toxicidade em células-tronco". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2015. http://hdl.handle.net/10183/149457.

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As plantas medicinais são consideradas importantes fontes de compostos biologicamente ativos. Para muitas doenças crônicas, como as neurodegenerações, substâncias que apresentam atividades simultâneas em mais de um alvo relacionado à etiopatologia dessas desordens, constituem potenciais agentes terapêuticos. Nesse contexto, os objetivos deste trabalho foram a avaliação química e biológica de três espécies de samambaias de ocorrência no sul do Brasil: Blechnum binervatum, B. brasiliense e B. occidentale. O isolamento bioguiado foi utilizado para a identificação da(s) substância(s) com potencial atividade em modelos in vitro e in silico relacionados às desordens neurodegenerativas. A avaliação dos extratos e frações permitiu destacar a fração acetato de etila de B. brasiliense como a mais ativa na estabilização de radicais hidroxila (CI50: 12,5 μg/mL) e na inibição da lipoperoxidação (CI50: 10,4 μg/mL), sendo uma das mais ativas frente ao óxido nítrico (CI50: 55,6 μg/mL). Adicionalmente, na inibição da isoforma A da enzima monoamina oxidase (MAO), esta fração foi a que apresentou menor valor de CI50 (28,6 μg/mL). As frações diclorometano também apresentaram bons resultados na inibição da MAO-A, sendo algumas ativas igualmente como antioxidantes. Frente à MAO-B, os extratos e frações das três espécies vegetais demonstraram menores efeitos e foram inativos frente às enzimas acetil e butiril colinesterase, não demonstrando toxicidade em células polimorfonucleares (PMN) de ratos Wistar, na concentração de 1 mg/mL. Utilizando células-tronco cultivadas, os extratos e frações selecionadas, nas concentrações de 100 a 500 μg/mL, não afetaram a viabilidade celular e não apresentaram efeitos tóxicos. Análises químicas por cromatografia líquida de alta eficiência, acoplada a detector de arranjo de diodos e espectrometria de massas, permitiram a identificação de isômeros dos ácidos cafeoil quínico e cafeoil chiquímico nos extratos das três espécies estudadas. B. binervatum apresentou, ainda, ácido cafeico glicosilado, ácido isosalvianólico A e ácido rosmarínico sulfatado. Ácido salvianólico F foi identificado em B. binervatum e B. occidentale, bem como isômeros do ácido brainico. Ácido rosmarínico foi caracterizado em B. binervatum e B. brasiliense. Quercetina 3-O-glicosídeo e vicenina-2 também foram identificadas. As análises por cromatografia gasosa, acoplada à espectrometria de massas demonstraram que o diterpeno neofitadieno foi o composto majoritário nas frações diclorometano de Blechunm e nas frações hexano de B. occidentale e B. binervatum. Para a fração hexano de B. brasiliense, β-sitosterol foi o principal componente. A partir da fração acetato de etila de B. brasiliense foi isolado o ácido rosmarínico, o qual se mostrou ativo nos ensaios de atividade antioxidante, na inibição da catecol-O-metil transferase (CI50: 26,7 μM) e da MAO-A (CI50: 50,1 μM), sendo proposto mecanismo reversível de inibição desta enzima. Nos estudos de docking foram verificadas as interações moleculares entre o composto e as enzimas MAO-A e COMT, por ligações de hidrogênio e interações hidrofóbicas nos sítios ativos enzimáticos. O composto não apresentou efeitos tóxicos em células PMN de roedores, nas concentrações de 0,5 e 5 mM. Os ácidos rosmarínico e clorogênico isolados do extrato de B. binervatum não influenciaram na viabilidade celular e não induziram efeito tóxico sobre células-tronco (100 a 500 μM), sendo que o ácido rosmarínico foi capaz, ainda, de induzir proliferação celular. Capacidade protetora contra danos celulares causados por H2O2 (1400 μM) foi observada para ambas as substâncias, nas concentrações de 10-100 μM, sendo os resultados corroborados pelas imagens de microscopia celular. O ácido rosmarínico apresentou melhores respostas quando comparado ao ácido clorogênico, sendo mais efetivo na inibição dos danos por H2O2. O conjunto dos resultados obtidos ressalta a importância dos estudos associados químico-biológico de espécies vegetais e aponta para as potencialidades de samambaias como fontes de produtos bioativos, capazes de atuar sobre múltiplos alvos enzimáticos e não-enzimáticos relacionados a doenças neurodegenerativas.
Medicinal plants are considered important sources of biologically active compounds. For many chronic diseases, such as neurodegenerations, substances that present simultaneous activities in more than one target related to the etiopathology of these disorders are considered potential therapeutic agents. In this context, the aims of the study were the chemical and biological evaluation of three fern species, occurring in south Brazil: Blechnum binervatum, B. brasiliense and B. occidentale. The bioguided isolation was employed to identify compound(s) with potential activities at in vitro and in silico models associated to neurodegenerative disorders. The biological evaluation of extracts and fractions allowed to highlight the ethyl acetate fraction of B. brasiliense, which was the most active in the stabilization of hydroxyl radicals (IC50: 12.5 μg/mL) and on lipoperoxidation inhibition (IC50: 10.4 μg/mL), being one of the most active sample against nitric oxide (IC50: 55.6 μg/mL). Furthermore, on the inhibition of isoform A from monoamine oxidase (MAO), this fraction showed the lowest IC50 value (28.6 μg/mL). The dichloromethane fractions also presented good results in the MAO-A inhibition, being some of them active as antioxidants, too. Against MAO-B, extracts and fractions of the three species demonstrated reduced effects and all samples were inactive in the acetyl and butyryl cholinesterase inhibition, showing no toxic effects to polymorphonuclear cells (PMN) from Wistar rats, at 1 mg/mL. Using cultured stem cells, the selected extracts and fractions at 100 to 500 μg/mL did not affect cell viability and absence of cytotoxic effects was observed. The chemical analysis by high performance liquid chromatography, coupled to photodiode array detector and mass spectrometry, allowed the identification of caffeoyl quinic acid and caffeoyl shikimic acid isomers in the three studied fern species. B. binervatum presented also glycosilated caffeic acid, isosalvianolic acid A and sulphated rosmarinic acid. Salvianolic acid F was identified in B. binervatum and B. occidentale, as well as, brainic acid isomers. Rosmarinic acid was characterized in B. binervatum and B. brasiliense. Quercetin 3-O-glycoside and vicenin-2 were also found. Analysis by gas chromatography with mass spectrometry showed the diterpene neophytadiene was the major compound in dichloromethane fractions of Blechunm and in hexane fractions of B. occidentale and B. binervatum. For the hexane fraction from B. brasiliense, β-sitosterol was majority. From the ethyl acetate fraction of B. brasiliense was isolated rosmarinic acid, which was shown to be active in antioxidant assays, in the inhibition of catechol-O-methyltransferase (IC50: 26.7 μM) and MAO-A (IC50: 50.1 μM), being suggested a reversible inhibition mechanism against this enzyme. In docking studies were observed molecular interactions between the compound and MAO-A and COMT enzymes, via hydrogen bonds and hydrophobic interactions in enzyme active sites. The compound did not induce toxic effects to rodent PMN cells, at concentrations of 0.5 and 5 mM. The rosmarinic and chlorogenic acids, isolated from B. binervatum extract, did not influence cell viability and did not induce toxicity to stem cells (100 to 500 μM), the rosmarinic acid was also capable to induce cell proliferation. Protective ability against H2O2-induced cell damage (1400 μM) was observed for both substances at concentrations of 10-100 μM, and the results were supported by cellular microscopy images. Rosmarinic acid presented better responses compared with chlorogenic acid, being powerful inhibitor against H2O2-induced damage. The overall results highlights the importance of associated chemical-biological studies of plant species and points at the potential of ferns as sources of bioactive compounds, capable of modulating multiple enzymatic and non-enzymatic targets related to neurodegenerative diseases.

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Caldú, i. Ferrús Xavier. "Influència de les variants genètiques de la COMT i el DAT en l'activació cerebral i en el processament cognitiu i emocional". Doctoral thesis, Universitat de Barcelona, 2007. http://hdl.handle.net/10803/2703.

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D'entre totes les catecolamines, la dopamina és la més important del sistema nerviós central, on regula funcions com la conducta motora, les emocions i la cognició. Donada la implicació del sistema dopaminèrgic en diverses disfuncions cerebrals, com ara l'esquizofrènia, la malaltia de Parkinson o el trastorn per dèficit d'atenció amb hiperactivitat, l'estudi d'aquest sistema ha esdevingut de gran importància. Els dos mecanismes més importants de terminació de l'activitat dopaminèrgica a nivell sinàptic són la recaptació mitjançant el transportador de la dopamina (DAT) i la degradació a través de la catecol-o-metiltransferasa (COMT). El gen del DAT presenta un polimorfisme consistent en un número variable de repeticions en tàndem (VNTR) de 40 parells de bases (bp). Aquest polimorfisme es troba en una regió no codificant del gen i, per tant, no està associat a mutacions en la seqüència d'aminoàcids de la proteïna, però sí s'han observat diferències en la disponibilitat de la proteïna associades al VNTR. Tot i que els estudis in vivo han estat poc concloents, els estudis in vitro suggereixen una major expressió de la proteïna associada a l'al·lel de 10 repeticions, la qual conduiria a menors nivells de dopamina sinàptica. La COMT és un enzim que pot catalitzar la metilació de petites molècules com fàrmacs, hormones i neurotransmissors o de macromolècules com les proteïnes, l'ARN o l'ADN. El gen de la COMT mostra un polimorfisme funcional causat per la transició d'una guanina a una adenina que suposa un canvi de l'aminoàcid valina per l'aminoàcid metionina al codó 108/158, depenent de si la forma de l'enzim codificada és la citosòlica (codó 108) o la membranal (codó 158). L'enzim que conté l'aminoàcid metionina és termolàbil a 37 ºC, mentre que l'enzim que conté l'aminoàcid valina mostra major estabilitat a temperatures entre els 37 i els 56 ºC. La major estabilitat comporta uns majors nivells d'activitat enzimàtica i, en conseqüència, una menor disponibilitat dopaminèrgica a nivell sinàptic. En els dos estudis que formen aquesta tesi vàrem avaluar l'efecte de les variants genètiques de la COMT i del DAT sobre l'activació cerebral relacionada amb la memòria de treball i el processament d'emocions, així com el seu impacte sobre les funcions cognitives prefrontals. A tal efecte, es va estudiar, mitjançant la tècnica de ressonància magnètica funcional (RMf) i l'administració de proves prefrontals, una mostra de subjectes sans dels quals s'havien obtingut prèviament el genotip per als polimorfismes Val108/158 Met de la COMT i 40 bp VNTR del DAT. Les anàlisis van mostrar una relació entre el genotip de la COMT i l'execució en el Wisconsin Card Sorting Tests (WCST). Concretament, el nombre d'al·lels Val estava relacionat amb un pitjor rendiment en aquest test, reflectit pel major nombre d'errors perseveratius. Pel que fa al genotip del DAT, es va observar un efecte sobre la variable temps de reacció del Continuous Performance Test (CPT). Els subjectes homozigots per a l'al·lel de 9 repeticions van ser els que van mostrar els temps de reacció més elevats, mentre que els subjectes homozigots per a l'al·lel de 10 repeticions van mostrar els temps de reacció més baixos. Tots dos genotips es van relacionar amb el nombre d'errors de comissió en el CPT. El nombre d'al·lels Val de la COMT i el nombre d'al·lels de 10 repeticions del DAT estaven relacionats amb un major nombre d'errors de comissió. Pel que fa a les dades de RMf no es va observar cap efecte dels genotips de la COMT i del DAT independentment, però sí un efecte additiu dels dos genotips sobre l'activació cerebral a la circumvolució frontal mitja (BA 9) durant la realització de l'N-back. Durant el processament d'emocions es va observar un efecte principal del genotip de la COMT en l'activació de l'amígdala dreta. Anàlisis posteriors van revelar una major activació de l'amígdala dreta en els subjectes homozigots per a l'al·lel Met en relació als portadors de l'al·lel Val. Els nostres resultats mostren, per tant, que les variacions genètiques que afecten la transmissió dopaminèrgica tenen un impacte sobre la fisiologia cerebral i sobre el rendiment cognitiu.

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Chau, Cecil Ming Yeung. "Neonatal pain and COMT Val158Met genotype in relation to serotonin transporter (SLC6A4) promoter methylation in very preterm children at school age". Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/55054.

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Children born very preterm are exposed to repeated neonatal procedures that induce pain and stress during hospitalization in the neonatal intensive care unit (NICU). The COMT Val158Met genotype is involved with pain sensitivity, and early life stress is implicated in altered expression of methylation of the serotonin transporter. We examined: (1) whether methylation of the serotonin transporter gene (SLC6A4) promoter differs between very preterm children and full-term controls at school age, (2) relationships with child behavior problems, and (3) whether the extent of neonatal pain exposure interacts with the COMT Val158Met genotype to predict SLC6A4 methylation at 7 years in the very preterm children. We examined the associations between the COMT genotypes, neonatal pain exposure (adjusted for neonatal clinical confounders), SLC6A4 methylation and behavior problems. Very preterm children had significantly higher methylation at 7/10 CpG sites in the SLC6A4 promoter compared to full-term controls at 7 years. Neonatal pain (adjusted for clinical confounders) was significantly associated with total child behaviour problems on the Child Behavior Checklist (CBCL) questionnaire (adjusted for concurrent stressors and 5HTTLPR genotype, p = 0.035). CBCL Total Problems was significantly associated with greater SLC6A4 methylation in very preterm children (p = 0.01). Neonatal pain (adjusted for clinical confounders) and COMT Met/Met genotype were associated with SLC6A4 promoter methylation in very preterm children (p = 0.001). These findings provide evidence that both genetic predisposition and early environment need to be considered in understanding susceptibility for developing behavioral problems in this vulnerable population.
Medicine, Faculty of
Graduate

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Godinez, Detre. "The Wisconsin Card Sorting Task: An analysis of the construct validity, heritability, and association with the COMT Val(158)Met polymorphism". Connect to online resource, 2007. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3273679.

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Kube, Johanna [Verfasser]. "Varianten im COMT-Gen und neue Urinmarker zur Risikoabschätzung der Entwicklung einer akuten und chronischen Nierenschädigung nach kardiochirurgischen Eingriffen / Johanna Kube". Magdeburg : Universitätsbibliothek, 2018. http://d-nb.info/1174626607/34.

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Wright, Galen Egan Buckley. "Molecular genetic analysis of two genes, CYP2D6 and COMT, in the schizophrenia-susceptibility locus on chromosome 22q in the Xhosa population". Thesis, Stellenbosch : Stellenbosch University, 2012. http://hdl.handle.net/10019.1/20366.

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Büttner, Claudia Sophia [Verfasser], i Caroline [Akademischer Betreuer] Jung-Sievers. "Assoziation von Polymorphismen im COMT-Gen mit der Schizophrenie und dem Arbeitsgedächtnis als Endophänotyp / Claudia Sophia Büttner. Betreuer: Caroline Jung-Sievers". München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2016. http://d-nb.info/1106854578/34.

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Daubitz, Torsten [Verfasser], i Andreas J. [Gutachter] Fallgatter. "Einfluss des COMT-Polymorphismus auf das Sensorische Gating bei erwachsenen ADHS-Patienten und gesunden Kontrollen / Torsten Daubitz. Gutachter: Andreas J. Fallgatter". Würzburg : Universität Würzburg, 2014. http://d-nb.info/1110028075/34.

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Akdenizli, Kemal [Verfasser]. "Bedeutung genetischer Polymorphismen in BDNF, Bcl-2 sowie COMT und MAO-A für den Erfolg der Therapie mit Antidepressiva / Kemal Akdenizli". Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2009. http://d-nb.info/1023783568/34.

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Armbruster, Diana. "The impact of serotonergic and dopaminergic genetic variation on endophenotypes of emotional processing". Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2010. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-63574.

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Decades of research in quantitative genetics have found substantial heritability for personality traits as well as for mental disorders which formed the basis of the ongoing molecular genetic studies that aim to identify genetic variations that actually contribute to the manifestation of complex traits. With regard to psychological traits, genetic variation impacting neurotransmitter function have been of particular interest. Additionally, the role of environmental factors including gene × environment interactions has been further investigated and the impor-tance of developmental aspects has been stressed. Furthermore, endophenotypes which link complex traits with their respective biological underpinnings and thus bridge the gap between gene and behaviour have begun to be included in research efforts. In accordance with this approach, this thesis aims to further examine the influence of genetic variation impacting serotonergic and dopaminergic functioning on endophenotypes of anxiety-related behaviour. To this end, two well established paradigms – the acoustic startle reflex and the cortisol stress response – were employed. Both show considerable interindividual variation which has been found in quantitative genetic studies to be at least partly based on genetic factors. In addition, the neural circuits underlying these endophenotypes are relatively well understood and thus reveal references for the detection of associated genetic influences. The results of this thesis associate the overall startle magnitude in two independent samples of young adults with a polymorphism in the promoter region of the serotonin transporter (5-HTT) gene (5-HTTLPR): Carriers of the short (S) allele which results in a reduced gene ex-pression showed a stronger startle magnitude which is in line with numerous findings linking the S allele to increased measures of negative emotionality. In addition to 5-HTTLPR, the effects of past stressful life events on the startle response were investigated: Participants who had recently experienced at least one stressful life event exhibited stronger startle responses and reduced habituation of the startle reflex although there was no 5-HTTLPR × environment inter-action effect. A third study revealed independent and joint effects of 5-HTTLPR and a poly-morphism in the dopamine receptor 4 gene (DRD4) in the same sample of young adults with regard to the cortisol stress response with carriers of the DRD4 7R allele which has been associ-ated with higher scores in sensation seeking, showing reduced cortisol responses. In addition, a 5-HTTLPR × DRD4 interaction effect emerged: 5-HTTLPR long (L) allele carriers showed the lowest cortisol response but only when they possessed at least one copy of the DRD4 7R allele. Moreover, in a fourth study a life span approach was taken and the influence of a further important serotonergic polymorphism which impacts the functioning of tryptophan hydroxylase 2 (TPH2), the rate limiting enzyme in the biosynthesis of serotonin, on interindividual differences in the startle response was investigated in three different age samples: children, young adults and older adults. There was a sex × TPH2 genotype interaction effect in a sample of young adults on the overall startle response while there was no effect of TPH2 in children or older adults. The last study of this thesis presents findings regarding the influence of two dopaminergic polymorphisms in genes encoding the enzyme catechol-O-methyltransferase (COMT) and the dopamine transporter (DAT), respectively, which both terminate dopamine signalling and are thus important regulators of dopaminergic neurotransmission, on the startle reflex in older adults. COMT met/met homozygotes showed the strongest and val/val homozygotes displayed the smallest startle magnitude which is in line with findings linking the COMT met allele to increased scores of anxiety related traits and disorders. Regarding DAT, participants homozygous for the 10R allele, which had previously associated with attention-deficit hyperactivity disorder, showed a stronger overall startle response. In sum, this thesis comprises data on interindividual differences in an electrophysiological and a hormonal endophenotype across the life span and their association with serotonergic and dopaminergic function based on genetic variation. One major finding is the clear evidence for the influence of serotonergic polymorphisms on the startle response in young adults while in contrast in older adults genetic variation in the dopaminergic system exerted considerable influence. These differences might be due to developmental processes in the different stages of life although cohort effects and effects of different recruitment strategies can also not be ruled out. Furthermore, there were significant differences regarding the genetic influence on the acoustic startle reflex and cortisol stress response in one and the same sample which might be due to methodological differences of the two paradigms as well as differences in their underlying neuronal circuits. In conclusion, this thesis supports the acoustic startle reflex and the cortisol stress response as valuable endophenotypes and thus indicators for underlying neurobiological circuits although some methodological issues remain. It also highlights the importance of taking developmental factors and changes over the course of life into account. Finally, this thesis emphasizes the necessity to include reliably and validly assessed past experienced events in molecular genetic studies in order to understand the interplay between genetic and environmental factors in shaping (endo)-phenotypes.

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