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1
Zhang, Yan. "Implementation of anti-apoptotic peptide aptamers in cell and "in vivo" models of Parkinson's disease." Thesis, Lyon, École normale supérieure, 2012. http://www.theses.fr/2012ENSL0788.
Повний текст джерелаАнотація:
La maladie de Parkinson (PD) est considérée comme la deuxième maladie neurodégénérative la plus fréquente. L'examen post-mortem de patients parkinsoniens et des modèles physiologiques d’études de la maladie de Parkinson suggèrent la participation de la mort cellulaire programmée, l'inflammation et l'autophagie dues au stress oxydatif, à des mutations ou l’agrégation de protéines au sein des neurones DA. Les aptamères peptidiques sont de petites protéines combinatoires, consistitués d’une plateforme (dans notre cas, la thiorédoxine humaine, hTRX) et une boucle variable insérée dans le domaine actif de hTRX. Deux aptamères peptidiques ont été identifiés par la sélection fonctionnelle. L’aptamère peptide 32 (Apta-32) ,est spécifique liant deux paralogues T32 impliqués dans le processus d'endocytose. L’aptamère peptidique 34(Apta-34) lie à une cible "T34", une protéine pro-apoptotique ayant un rôle dans la voie apoptotique provenant du noyau. Le travail de cette thèse visait à étudier la fonction anti-apoptotique de nos deux aptamères peptidiques dans deux modèles d’étude de la maladie de Parkinson: un modèle cellulaire (in vitro) et un modèle transgénique D. melanogaster (in vivo). Deux toxines majeures ont été appliquées dans ce travail, 6-hydroxindopamine (6-OHDA) et le paraquat, un pesticide couramment utilisé. Nos observations montrent que la drosophile exprimant Apta-32 dans tous les neurones ont montré une meilleure résistance après 48h de traitement avec le paraquat comparé à deux autre aptamères peptidiques, Apta-34 et Apta-TRX (sans boucle de contrôle variable). Une autre étude a révélé un défaut dans la phagocytose des corps apoptotiques au cours du développement embryonnaire de la drosophile exprimant Apta-32 dans les macrophages, ce qui suggère qu’Apta-32 pourrait participer à et peut-être interférer avec le processus de l’autophygie, et que Apta-32 pourrait protéger contre l'autophagie induite par paraquat dans les neuronesParkinson’s disease is considered as the second most common neurodegenerative disease. Although the cause of the progressive cell loss of PD remains unclear to date, programmed cell death, inflammation and autophagy due to oxidative stress, gene mutations or protein aggregations within DA neuron have been suggested as potential causes. Peptide aptamers are small combinatorial proteins, with a variable loop inserted into a scaffold protein, human thioredoxin, hTRX. They are used to facilitate dissection of signaling networks by modulating specific protein interactions and functions. Two peptide aptamers were identified by functional selection which inhibit Bax-dependent cell death in mammalian models. One peptide aptamer (Apta-32) is binding two paralogues involved in endocytotic trafficking T32. The second peptide aptamer (Apta-34) is binding to a target "T34", a pro-apoptotic protein mediating apoptosis emanating from the nucleus. The work of my PhD thesis aimed to investigate the anti-apoptotic function of our two peptide aptamers in different PD models including cell model (in vitro), brain tissue slice and D. melanogaster (in vivo) ; in particular their impact on neuron survival after exposure to specific toxins. Two major toxins were applied in this work, 6-hydroxindopamine (6-OHDA) and Paraquat, a commonly used pesticide. Our observations indicated that Drosophila expressing Apta-32 in all neurons showed more resistance 48h after treatment with Paraquat, compared to drosophila expressing Apta-34 or TRX. Another study revealed a defect in phagocytosis of apoptotic bodies in drosophila embryo’s expressing Apta-32 in macrophage, suggesting Apta-32 could be involved in, and perhaps interfere with, the process of autophagy. This suggests that Apta-32 could protect against paraquat induced autophagy in neurons
2
Hobani, Yahya Hasan. "Metabolomic analyses of Drosophila models for human renal disease." Thesis, University of Glasgow, 2012. http://theses.gla.ac.uk/3222/.
Повний текст джерелаАнотація:
Inborn errors of metabolism (IEMs) constitute a major class of genetic disorder. Most of IEMs are transmitted recessively, so consanguinity has a huge impact on disease prevalence, particularly in societies like Saudi Arabia, where consanguineous marriage is common. Understanding and treatment are very important in genetic diseases, and simple models would be helpful. Thus, the feasibility of applying the fruit fly, Drosophila melanogaster, as a model for a human renal genetic disease - xanthinuria - was investigated. Xanthinuria is a rare human genetic disease, caused by mutations in xanthine oxidase or molybdenum cofactor sulphurase; in Drosophila, the homologous genes are rosy (ry) and maroon-like (mal), respectively. The new Orbitrap technology of mass spectrometry has the potential to determine levels of many metabolites simultaneously by exact mass, and a major part of this thesis was to investigate the utility of Orbitrap technology in metabolomics of both wild-type and Drosophila mutant. Repeatable significant differences were identified between ry and wild-type flies, which recapitulated painstaking analytical biochemical determinations of the 1950s, but with greater precision. Additionally, completely novel impacts of the ry mutation (on pyrimidine metabolism, the urea cycle and osmolyte biosynthesis) were identified. As expected mal mutants showed more similar changes as ry, but with widespread metabolic perturbations. The online resource, FlyAtlas.org, provides detailed microarray-based expression data for multiple tissues and life-stages of Drosophila. Downstream genes, such as urate oxidase, are utterly tubule-specific. Accordingly, the utility of Orbitrap technology in elucidating tissue-specific metabolomes was also investigated. Additionally, genetic interventions using designed RNAi constructs were also made and validated by QPCR and metabolomics. As urate is a potent antioxidant, survival of urate oxidase knockdowns was tested in vivo, and a significant impact on survival identified. An Affymetrix microarray was performed, comparing ry506 mutant flies against wild-type and differences were identified in a second experiment, the anti-gout drug allopurinol was used to phenocopy the effects of ry. Overall, the thesis showed that Orbitrap technology was highly suitable for metabolomic analysis of both wild-type and mutant Drosophila, and had potential in the analysis of metabolomes of single tissues. The possibility of using Orbitrap-based metabolomicsin human diagnosis is discussed.
3
Vargas, Miguel. "Nutrient response and aging in invertebrate models." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/nutrient-response-and-aging-in-invertebrate-models(3fccf140-7906-4fad-9892-b8957dc44a04).html.
Повний текст джерелаАнотація:
The diet an organism keeps is crucial in sustaining its health and fitness. The fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans are excellent models for nutritional studies due to their small size, large progeny numbers, quick development, and modifiable laboratory diets. Here I examine these two organisms in order to better understand the complex interrelationship between an animal and its diet. Previous work has shown that in the wild numerous organisms are capable of selecting specific nutrients in a non-random manner in order to maximize fitness. However, the genetic underpinnings driving these nutrient choices remain elusive. Female fruit flies consume higher levels of protein following mating to prepare for the costs of reproduction. I examined the role of S6 Kinase (S6K), a downstream effector of the nutrient-responsive target of rapamycin pathway, in mediating this decision. I demonstrate that neuronal S6K activity and serotonin are involved in regulating protein consumption when allowed to choose nutrients freely as well as following macronutrient deprivation; suggesting that they may play a role in mediating postmating dietary switch and maintaining nutrient balance. Modulating levels of dietary components can have extensive impacts on processes such as development, fecundity, and metabolism in multiple organisms. However, the influence of dietary genetics on the consumer is virtually unknown. I performed a screen feeding single-gene mutants of E. coli to C. elegans and monitored the effects on the insulin-like signalling pathway (ILS). When mutated, genes involved in multiple processes and functions in E. coli enhanced activity of the ILS downstream transcription factor, DAF-16. One mutant strain of E. coli I pursued had a knockout of the cAMP-producing, adenylate cyclase gene. Addition of exogenous cAMP to the diet containing live, metabolically active E. coli rescued all the effects of the mutant on C. elegans; thereby suggesting that bacterial metabolism of dietary cAMP can influence the C. elegans ILS. Collectively, my work demonstrates how the nutrient-sensing pathways of the consumer can shape and be shaped by interactions with its diet. These studies contribute to a better understanding of the consumer-diet relationship, and could help guide future work to investigate the role of diet in disease, quality of life, and longevity.
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Snigdha, Kirti. "Study of Tumor Development Using Drosophila melanogaster Models." University of Dayton / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=dayton1591210557481631.
Повний текст джерела
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Xun, Zhiyin. "Understanding Parkinson's disease through proteome analyses of Drosophila melanogaster models." [Bloomington, Ind.] : Indiana University, 2008. 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:3344612.
Повний текст джерелаАнотація:
Thesis (Ph. D.)--Indiana University, Dept. of Chemistry, 2008.Title from PDF t.p. (viewed Oct. 7, 2009). Source: Dissertation Abstracts International, Volume: 70-02, Section: B, page: 0993. Adviser: David E. Clemmer. Includes supplementary digital materials.
6
Michel, Claire Hélène Marie. "Investigating inflammation in a Drosophila model of Alzheimer's disease." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608998.
Повний текст джерела
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Girard, Victor. "Understanding lipid droplet biogenesis in the central nervous system of Drosophila models of Parkinson's disease." Thesis, Lyon, 2020. http://www.theses.fr/2020LYSEN083.
Повний текст джерелаАнотація:
Les maladies neurodégénératives sont l’une des principales causes d’invalidité dans le monde. Certaines de ces maladies, telle que la maladie de Parkinson (MP), sont associées à des dérégulations du métabolisme lipidique. En effet, plusieurs laboratoires dont le nôtre, ont montré que l’accumulation d’acide gras sous forme de gouttelettes lipidiques (GLs) dans les cellules gliales est un mécanisme de réponse au stress oxydatif conservé au cours de l’évolution. De plus, la formation de GLs dans les neurones pourrait aussi participer au processus neurodégénératif. La contribution respective des cellules gliales et des neurones reste cependant peu étudiée. Au cours de ma thèse, je me suis intéressé aux mécanismes et conséquences pathologiques de l’accumulation de GLs dans les neurones et les cellules gliales. La MP est caractérisée par l’accumulation d’alpha-synucléine (aSyn) sous forme d’agrégats intracellulaires appelés corps de Lewy. L’aSyn est une protéine normalement localisée aux synapses contenant un domaine de liaison aux lipides. L’aSyn peut se lier à la surface des GLs in vitro et l’expression d’aSyn humaine dans la levure induit l’accumulation de GLs. Cependant, la conservation et relevance de ce processus dans le cadre de la MP restent à démontrer. Durant ma thèse, j’ai montré que l’expression simultanée de l’aSyn et de périlipine, une protéine de surface des GLs, induit l’accumulation de GLs dans les neurones photorécepteurs de la rétine de drosophile. De plus, l’aSyn se localise à la surface des GLs dans les photorécepteurs de drosophiles et les neuroblastes humains en culture. Mes résultats suggèrent que l’association de l’aSyn et des périlipines aux GLs, pourrait les stabiliser et favoriser leur accumulation. Enfin, la présence de GLs dans les photorécepteurs augmente la résistance de l’aSyn à la digestion par protéinase K, suggérant que les GLs sont impliquées dans la conversion pathologique de l’aSyn vers des formes agrégées.Les cellules gliales maintiennent l’intégrité du système nerveux central et peuvent accumuler des GLs en réponse à des dommages neuronal ou du stress. J’ai montré que Split-ends (Spen), une protéine identifiée comme facteur de survie des cellules gliales au cours du développement, est impliquée dans le maintien de l’homéostasie des GLs dans les cellules gliales de drosophile adulte. De plus, l’expression de spen promeut la résistance des mouches au traitement par le Paraquat, un pesticide reconnu comme facteur de risque pour la MP chez l’homme. Ces résultats suggèrent que les fonctions de spen dans le maintien de l’homéostasie lipidique dans les cellules gliales protègent contre le stress oxydatif induit par le paraquat.Collectivement, les résultats obtenus au cours de ma thèse montrent que le maintien de l’homéostasie des GLs dans les cellules gliales mais également dans les neurones est important dans les processus pathologiques associés à la MPNeurodegenerative disorders are a worldwide leading cause of disability. Several neurodegenerative disorders including Parkinson's disease (PD) are associated with lipid storage dysregulation in the brain. In particular, the storage of lipids in cytoplasmic organelles, called lipid droplets (LDs), has recently emerged as important mechanism of the stress response. Several labs including ours, found that LD accumulation in glia may promote neuronal survival in condition of oxidative stress. Interestingly, in the context of neurodegeneration, neurons can also accumulate LDs. The contribution of neuronal and glial cells LDs to neurodegeneration remains a topic of debate. During my PhD, I investigated the mechanisms and consequences of LD accumulation in neurons and glia in two Drosophila models of PD. PD is characterized by the accumulation of misfolded alpha-synuclein (aSyn) in neuronal cytoplasmic inclusions. Interestingly, aSyn contains a lipid-binding domain that shares structural similarities with LD-binding proteins such as perilipins and aSyn can bind synthetic LD in vitro and induces LD accumulation in yeast by a mechanism that remains unclear. I found that expression of aSyn in association with perilipin impairs LD homeostasis leading to accumulation of LDs in Drosophila photoreceptor neurons. Interestingly, I observed that aSyn co-localizes with perilipins on LD surface in both Drosophila photoreceptor neurons and human neuroblastoma cells. I thus proposed that aSyn by associating with perilipins stabilize LD and by this mean promote LD accumulation. Finally, modulating LD content in photoreceptor impacts aSyn resistance to proteinase K suggesting that LDs are involved in pathological conversion of aSyn. Glial cells are early sensor of central nervous system injuries that accumulate LDs in response to neuronal stress to protect neurons from damages associated with lipid peroxidation. We found that Split-ends (Spen), an RNA binding protein previously identified as a glial pro-survival factor during development, maintains LD homeostasis in adult glial cell. In addition, expression of spen was associated with resistance to paraquat-induced neurotoxicity, a pesticide associated with increased risk of PD in human epidemiologic studies. These results suggest that Spen-mediated lipid metabolism functions is important for neuroprotection in PD.Collectively the results of my thesis provide new evidences for the formation of LDs in both neurons and glial cells and their contribution in the progression of PD pathology
8
Ferlito, Valentina Claudia. "Evaluating the potential for neurodegenerative disease models in juvenile Drosophila melanogaster." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28834.
Повний текст джерелаАнотація:
With 9.9 million new dementia cases each year, Alzheimer’s and Parkinson’s disease (AD and PD) are the most prevalent form of neurodegenerative disorder (NDG) affecting the aging population. Despite years of pharmaceutical research, no cure is yet available. Most neuropathological aspects of these diseases are extremely complex but the study of the rare genetic cases allowed to model these diseases in animals and uncover key pathophysiological processes. Transgenic Drosophila NDG models have been used for in vivo studies for many years with a range of relevant phenotypes. The cellular and molecular biology of the Central Nervous System, as well as the mechanisms underlying neurodegeneration, are well conserved between Drosophila and Humans (with a 75% of human disease-related genes having homologs in flies). Most NDG studies are performed in the aging flies. However, there are reports of measurable phenotypes for a variety of AD and PD models in juvenile Drosophila melanogaster (larval stage) with an unexploited considerable potential for drug discovery and screening for this outstanding model. Here I sought to develop a new assay for research into NDGs that focus on the earliest phenotypes. During this Ph.D. project a customized crawling assay apparatus was developed, for the assessment of locomotor ability in humanised larval Drosophila (overexpressing human proteins/peptides linked to AD and PD). A locomotor phenotype was identified in larvae overexpressing different variation of Amyloid-β42, tau and α-Synuclein pan neutrally: these animals crawl on agarose surface at a reduced mean speed when compared to controls. The defect was proven partially rescuable by administration of Tacrine and Methylene Blue, renewing the importance of such models for future applications in drug discovery and screening. The motor impairment supports the hypothesis of a neurotoxic effect of the protein/peptide. Thus, to test this further, the overexpression of the human transgenes was restricted to neurons involved in larval olfaction (olfactory impairment is often the earliest symptom in PD and AD) and odour associated learning tasks (both PD and AD are characterized by severe cognitive dysfunction). Interestingly, larvae overexpressing the Amyloid-β42 ARC peptide in the Olfactory Sensory Neurons showed a subtle navigation defect during chemotaxis (in 1-Hexanol odour gradient) that could possibly be addressed to premature neural habituation to the olfactory stimulus. Furthermore, the overexpression of the peptide in the larval Mushroom Bodies influenced the performances of the animals in associative learning tasks. Lastly, using immunohistochemistry and confocal imaging techniques I showed that the gross morphology of neurons is not altered by the targeted overexpression of the Amyloid-β42 ARC. Even though physiological studies are required to characterize the chemosensory/learning defect shown by the Amyloid-β42 ARC larvae, this Ph.D. work further confirms that the effects of the overexpression of the human transgenes are robust and measurable already at larval stage. These findings may also be relevant to the development of new, fast, and cost-effective compound screening procedures, for applications in early stages of the drug discovery process.
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Page, Richard Mark Donald. "Pathways of amyloid-β neurotoxicity in a Drosophila model of Alzheimer's disease". Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612858.
Повний текст джерела
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MacLeod, Ian. "A Drosophila model of familial encephalopathy with neuroserpin inclusion bodies." Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611439.
Повний текст джерела
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Nehrkorn, Johannes [Verfasser], and Andreas [Akademischer Betreuer] Herz. "Olfactory learning in Drosophila : learning from models / Johannes Nehrkorn. Betreuer: Andreas Herz." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2016. http://d-nb.info/108250498X/34.
Повний текст джерела
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Limmer, Stéfanie. "Study of host pathogen relationships in intestinal infection models of Drosophila melanogaster." Strasbourg, 2010. http://www.theses.fr/2010STRA6103.
Повний текст джерелаАнотація:
S. Marcescens ingérée par la mouche la tue en six à huit jours. Afin d'identifier les facteurs de l'hôte impliqués dans le processus infectieux, nous avons mis en oeuvre un crible compréhensif à l'échelle du génome basé sur l'interférence ARN (ARNi) in vivo dans des mouches transgéniques. Ce crible a été réalisé à Vienne en collaboration avec le groupe dirigé par le Pr. J. Penninger (IMBA, Vienne), essentiellement par Nadine Nehme et Shane Cronin. Un crible secondaire concentré sur les gènes candidats possédant des homologues chez les vertébrés et présentant un phénotype lorsque leur expression était ciblée seulement dans l'intestin moyen a permis de restreindre la liste, laquelle contenait plusieurs gènes de la voie JAK-STAT. Nous avons établi que la voie JAK-STAT contrôle le taux de prolifération des cellules souches intestinales au cours de l'infection. Pseudomonas aeruginosa tue la mouche en huit à dix jours après ingestion. La forte prolifération des bactéries dans l'hémolymphe induit les deux voies de la réponse humorale systémique, Toll et Immune Deficiency (IMD). La réponse cellulaire est aussi impliquée. Des bactéries mutants pour le gène rhIR, lequel est requis dans un système de perception du quorum sont monis virulent. La virulence des bactéries rhIR est seulement rétablit dans des mouches dépourvues de réponse cellulaire sont infectées. Nos résultats établissent que le gène rhIR est nécessaire essentiellement pour contrebalancer la seule réponse cellulaire et non la réponse humoraleS. Marcescens fed to the fly are killing in 6-8 days. To better understand the host factors implicated in the infection process we performed an ill vivo genome-wide RNAi (RNA interference) screen. This screen was realized in collaboration with the Penninger lab (Vienna). A secondary screen on the candidate genes that have vertebrate homolgs (mouse or human) was carried out using a midgut-specific driver to express the RNAi hairpin constructs. Amongst the genes that showed, in addition to the primary screen, a phenotype in the intestine specific screen, were several members of the JAK-STAT pathway. We were able to show that the JAK-STAT pathway is needed to control the level of compensatory proliferation of ISCs during the infectious process. P. Aeruginosa kills the flies within 8-\0 days upon ingestion. A strong proliferation of the bacteria in the hemolymph induces the two pathways of the humoral systemic immune response, Toll and Immune Deficiency (IMD). Phagocytosis is also needed for host defense. Bacteria mutant for the gene rhIR are less virulent. RhIR mutant bacteria just regain their virulence in flies deficient for phagocytosis. Our results show that RhIR is needed to counteract the cellular immune response, but not the humoral immune response
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Afzal, Mahmood Qurat-ul-ain. "Investigation of the effects of MFN2 mutations in cellular and Drosophila models." Thesis, University of Sheffield, 2015. http://etheses.whiterose.ac.uk/10760/.
Повний текст джерелаАнотація:
Mitochondria continuously undergo changes in their morphology by two dynamic processes called mitochondrial fusion and mitochondrial fission. Mitochondrial fusion results in longer mitochondria and is important for the complementation of mtDNA and intermixing of essential mitochondrial proteins and nutrients to maintain healthy mitochondrial population. Mfn1 and Mfn2 are involved in outer mitochondrial membrane fusion while OPA1 mediates inner mitochondrial membrane fusion. On the other hand, mitochondria are broken into smaller units for easy transport and removal of damaged mitochondria by Drp1. Defective mitochondrial dynamics has been linked with various common neuropathies and neurodegenerative diseases. Charcot Marie Tooth Type 2A (CMT2A) and its subtype Hereditary motor and sensory neuropathy type VI (HMSNVI) are caused by mutations in Mfn2 and result in progressive loss of distal motor and sensory neurons of peripheral nervous system. However, the pathomechanism of Mfn2 mutations and specific degeneration of peripheral motor and sensory neurons is still unclear.
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Irving, Andrew David. "General methods for large biological networks applied to fruit fly models." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/general-methods-for-large-biological-networks-applied-to-fruit-fly-models(5eb3812e-f2dc-488b-bba4-fa0f094d4776).html.
Повний текст джерелаАнотація:
A key part of a fruit fly's development is the formation of segmentsin its body. These structures are built by the protein forms of so-called segment polarity (SP) genes. It is the asymmetric expression of SP genes which creates the fruit-fly's segmental structure. The SP genes and their products (e.g. proteins) can be said to form a system which is self-regulating, i.e. genes are used to make proteins and, in turn, proteins are used to turn genes on or off. How this system achieves stable asymmetry of this kind is mathematically interesting as it can be thought of in a different way - multiple symmetries in the same system. This is unusual and we attempt to explain how it is possible using a mathematical model constructed by von Dassow et al. When trying to understand a biological system of this kind, there are two main approaches - reductionist and holistic. We try to show that they are not mutually exclusive - we look at the whole system but reduce what is meant by the whole. For example, von Dassow's model is large scale and, using it as a template, we show that a similar (but smaller) model inherits its properties. Smaller models can be made by short-handing the translation process (through which RNA is used to make protein) wherever an SP gene has a unique protein form. Our data indicates that the simultaneous wild-type expression of key SP genes (engrailed and wingless) takes place only when cumulative regulation of the wingless gene by two SP proteins is weak. The absence of this regulation would explain coexistence of multiple mathematical symmetries in one system (representative of genetic asymmetry) as it acts like a division between them. In this way, the system itself can be thought to divide into two independent sub-systems which can be treated separately.
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Krench, Megan Attardo. "Investigating toxicity in Drosophila models of Huntington's Disease and Huntington's Disease-Like 2." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/103211.
Повний текст джерелаАнотація:
Thesis: Ph. D. in Neuroscience, Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2016.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 247-264).
The polyglutamine diseases are the most common form of inherited neurodegenerative disorders. Each of the polyglutamine diseases stems from the same underlying cause: a CAG expansion mutation in the coding region of a gene. This gives rise to a protein with an expanded glutamine repeat stretch. Despite the fact that all polyglutamine diseases are caused by the same type of mutation, the CAG expansion in different genes gives rise to different diseases, with differentially vulnerable neuronal populations and distinct pathologies. One of the most well-known polyglutamine disorders is Huntington's disease (HD), which results from a CAG repeat expansion in the huntingtin (Htt) gene. HD is characterized by psychiatric symptoms, cognitive decline, and movement disturbances, especially chorea. Interestingly, some presumed HD patients exhibited HD-like symptoms and characteristic striatal degeneration, but did not harbor a mutation in Htt. This led to the discovery of the Huntington's disease-like (HDL) disorders. One such disorder is Huntington's disease-like 2 (HDL2). Recent studies identified a specific polyglutamine protein hypothesized to contribute to HDL2 pathology. Given the similarities between HD and HDL2 patients, I used Drosophila to model these two genetically distinct disorders to compare polyglutamine-induced toxicity. This work represents the first time HDL2 has been modeled in Drosophila, and the first characterization of HDL2 polyglutamine protein pathology. My investigation highlights many distinctions between expanded Htt and HDL2 polyglutamine proteins. Importantly, my research demonstrates that nuclear localization of the polyglutamine protein is critical to disease pathogenesis in HDL2, but not HD. I also present the results from an in vivo RNAi screen to search for novel suppressors of toxicity in our HD and HDL2 models. Analyzing top RNAi suppressors from both models indicates different pathogenic pathways are at play in these two polyglutamine diseases, but some mechanisms may be shared. We conclude that while HD and HDL2 have similar clinical profiles, distinct pathogenic mechanisms contribute to the two neurodegenerative disorders.
by Megan Krench.
Ph. D. in Neuroscience
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Moens, Thomas Grover. "Molecular mechanisms of pathogenesis in Drosophila models of C9orf72 mutation associated ALS/FTD." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10046295/.
Повний текст джерелаАнотація:
A GGGGCC hexanucleotide repeat expansion within the C9orf72 gene is the most common genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). Toxicity has been proposed to be due to loss of function of the gene, or by a toxic gain of function, mediated either by the transcription of repetitive sense and antisense RNA molecules, or by translation of RNA into five repetitive dipeptide proteins (DPRs) via repeat associated non-ATG initiated translation. In order to fully assess the role of sense and antisense RNA in vivo, Drosophila models were created where expression of sense or antisense RNA was induced whilst suppressing the formation of DPRs. Despite the formation of cardinal pathological features (RNA binding protein sequestering intranuclear RNA foci) toxicity was not observed in these models suggesting that repeat RNA plays a limited role in disease pathogenesis. When individual DPRs are expressed in Drosophila neurons a strong toxicity is induced by the arginine containing DPRs (poly-GR and poly-PR). To gain insight into the mechanism(s) by which this toxicity occurs, the protein-interactome of these DPRs was investigated in vivo using novel transgenic Drosophila that inducibly express affinity tagged DPR constructs, with identification of interacting proteins using mass spectrometry. In parallel, inclusions of dipeptide proteins were laser-capture microdissected from patient brain tissue and enriched proteins identified by mass spectrometry. The overlap of these datasets suggested that translation may be impaired by the arginine-containing DPRs and methods were adapted to assess the rate of translation in adult Drosophila brains. In parallel, enzymelinked immunosorbent assays (ELISAs) were developed against poly-GR and an abundant non-toxic DPR poly-GP. Measurement of these proteins was performed in various model systems (transfected immortalised cell lines, induced pluripotent stem cell derived neurons, Drosophila models) to confirm the validity of the assays and the potential therapeutic value of interventions.
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Polo, Carla Cristina 1987. "Caracterização molecular de domínios funcionais de miosinas de drosophila melanogaster." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/314549.
Повний текст джерелаАнотація:
Orientador: Mário Tyago MurakamiDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia
Made available in DSpace on 2018-08-20T10:58:02Z (GMT). No. of bitstreams: 1 Polo_CarlaCristina_M.pdf: 4286137 bytes, checksum: cf12a2b67d90255468d1906d719759a3 (MD5) Previous issue date: 2012
Resumo: As miosinas pertencem a uma família de proteínas motoras que através da hidrólise de ATP são capazes de se movimentarem pelas fibras de actina. Sua estrutura é dividida em três domínios principais: motor, responsável pela hidrólise do ATP; regulador, envolvido na ligação de cadeias leves de calmodulina e a cauda, que tem papel essencial na mediação de interações com cargas celulares, como organelas, ácidos nucleicos e outras proteínas. O organismo modelo para insetos, Drosophila melanogaster, possui 11 miosinas pertencentes a 8 classes sendo que informações funcionais e bioquímicas são escassas, e estruturais, inexistentes. Apesar dos grandes avanços obtidos nos estudos de miosinas humanas, as miosinas de inseto ainda são pouco caracterizadas não havendo estudos comparativos, como por exemplo, para a determinação de conservação de parceiros moleculares entre os diferentes filos da classificação de Lineu. Neste contexto, foram selecionados os seguintes domínios de inseto para caracterização molecular: quinase da miosina III, cauda globular da miosina V e FERM da miosina XV. A partir do cDNA da pupa e adulto do inseto foram amplificados os fragmentos de genes de interesse e clonados em vetor de clonagem, pGEM T-easy, e posteriormente de expressão, pET28a e pET28aSUMO. Após testes em diversas condições no sistema bacteriano, as construções cauda globular da miosina V (GLOB_2 e GT-f) e domínio FERM-f da miosina XV foram obtidos na fração solúvel e com rendimento suficiente para estudos estruturais. O protocolo de expressão em larga escala assim como de purificação foram estabelecidos para cada uma dessas construções. Estudos biofísicos por aSEC, DLS, CD e SAXS foram realizados para a proteína GT-f da miosina V, mostrando a proteína monomérica com alto conteúdo de hélices-alfa corroborando as análises in silico e com as caudas globulares de miosinas ortólogas já descritas. Além disso, sua termoestabilidade foi avaliada com Tm de 46 ºC e que sua estabilidade é alterada pela adição de alguns ligantes, mas não pela força iônica como verificado para a cauda globular da miosina Va humana. A estrutura a baixa resolução da GT-f foi determinada pelos experimentos de SAXS, mostrou uma proteína monomérica com forma alongada (Dmax =100 Å). Para a construção FERM-f, apesar do sucesso alcançado no protocolo de expressão e purificação, a amostra permaneceu polidispersa e com uma estrutura random coil, inviabilizado futuros experimentos. Acredita-se que a ausência do domínio MyTH4, gerou a perda de estabilidade do domínio FERM-f e será necessária a clonagem dos dois domínios fusionados para garantir a estabilidade estrutural e funcional
Abstract: Myosins belong to a motor protein superfamily that uses the ATP hydrolysis to move along actin filaments. Its structural architecture comprises three main domains: motor, responsible for ATP hydrolysis; regulator, which binds calmodulin light chains; and tail, responsible for cellular cargoes binding. Drosophila melanogaster, an insect model, has 11 myosins belonging to 8 different myosin classes; however functional and biochemical data are scanty, and, structural, absent. Although the great advances on investigating human and yeast myosins with the elucidation of molecular partners and molecular mechanisms involved in signaling, there are no comparative studies among different phyla. Therefore, in order to gain insights into insect myosins, in silico analysis were performed and some domains like kinase (myosin III), globular tail (myosin V), and FERM (myosin XV) were selected for biophysical and structural studies. From pupa and adult cDNAs, the target genes were amplified and cloned into pGEM- T-easy, pET28a and pET28aSUMO vectors. After expressions tests, the myosin V globular tail constructs, GLOB_2 and GT-f, and myosin XV FERM-f were obtained in soluble fraction and in sufficient amounts for structural studies. aSEC, DLS, CD e SAXS biophysical studies were performed to myosin V GT-f, showing that the protein is monomeric with predominance of alpha-helix in accordance with the in silico atomic model. The stability of GT-f was assessed with a Tm of 46 ºC and some molecules are able to increase the stability, while the ionic strength has no difference like was observed for the human globular tail of myosin Va. The low resolution structure determined by SAXS experiments confirmed the monomeric state and its elongated molecular shape (Dmax = 100 Å). The FERM-f construct, although the purification and expression protocol were standardized, the sample remained polydisperse with a random coil structure, disabling other biophysical experiments. It is supposed that the absence of the MyTH4 domain in the FERM-f domain results in loss of stability, and cloning and expression of fused domains will be necessary to guarantee structural and functional stability
Mestrado
Bioquimica
Mestre em Biologia Funcional e Molecular
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Laurent, Stefan. "Statistical inference of complex demographic models in Drosophila melanogaster and two wild tomato species." Diss., lmu, 2011. http://nbn-resolving.de/urn:nbn:de:bvb:19-126410.
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Martinez, Zarate A. "Parkinson's disease-associated proteins : studying their role in mitophagy with cellular and Drosophila models." Thesis, University of Liverpool, 2017. http://livrepository.liverpool.ac.uk/3007480/.
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Solomon, Daniel Adam. "Mechanisms of G4C2 derived dipeptide repeat protein toxicity in Drosophila models of C9ALS/FTD." Thesis, King's College London (University of London), 2018. https://kclpure.kcl.ac.uk/portal/en/theses/mechanisms-of-g4c2-derived-dipeptide-repeat-protein-toxicity-in-drosophila-models-of-c9alsftd(fe890a3c-a4a0-42c7-b2fc-7780889fc2b9).html.
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A G4C2 hexanucleotide repeat expansion in the gene C9ORF72 is the most common cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD). Although intronic, the G4C2 repeat is translated in the absence of an ATG start codon through a mechanism known as repeat-associated non-ATG translation resulting in the production of five different dipeptide-repeat proteins (DPRs). These DPRs form inclusions in brains of C9+ ALS and FTD sufferers. Further, C9+ patients are also characterised by cytoplasmic inclusions of the protein TDP-43, whose dysfunction is causally related to ALS and FTD. However, the pathogenic mechanisms underlying C9ALS/FTD and its relation to TDP-43 remain elusive. I have characterised numerous transgenic Drosophila to study G4C2 and DPR toxicity, and its relation to TDP-43 dysfunction. These Drosophila models of C9ALS/FTD are characterised by behavioural deficits that varied in age of onset and severity. The characteristics of motor impairment and subsequent neurodegeneration were dependent on the levels and identity of DPRs produced rather than G4C2 RNA. Severe, early onset phenotypes correlated with the presence of poly-GR whereas high levels of poly-GP and poly-GA correlated with late onset phenotypes. Non-G4C2 derived poly-GR caused a cytoplasmic accumulation of Drosophila TDP-43 (TBPH) whilst non-G4C2 derived poly-GA sequestered TBPH into inclusions. No change in TBPH localisation was seen following G4C2 RNA expression only. These alterations were accompanied with changes in the localisation of importins α2 and α3, the Drosophila homologues of karyopherins KPNA2 and KPNA4, respectively. However, expression and localisation of nucleocytoplasmic transport components such as RanGAP and nuclear pore complex proteins previously implicated in C9ALS/FTD appeared unperturbed. Further, cytoplasmic mislocalisation of TBPH enhanced DPR levels and cytotoxicity. Similar phenotypes were observed for patient frontal cortex in sporadic FTD and C9FTD; with KPNA4 being depleted from the nucleus and overlapping with TDP-43 inclusions. Taken together, these findings establish DPR accumulation as a cause of TDP-43 proteinopathy.
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Varga, Scott J. "An Analysis of the Potential Rescue Effects of Optogenetic Approaches in Drosophila Models of Parkinson's Disease." Ohio University Honors Tutorial College / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ouhonors1366924643.
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Waghmare, Indrayani. "Investigation of Altered Cell-Cell Interactions and Signaling Mechanisms in Drosophila Tumor Models." University of Dayton / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=dayton1467810236.
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Schindler, Franziska [Verfasser]. "Analysis of mutant huntingtin aggregation and toxicity in Drosophila models of Huntington’s disease / Franziska Schindler." Berlin : Freie Universität Berlin, 2017. http://d-nb.info/1127046225/34.
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Dulcis, Davide. "The Drosophila and Manducahearts as models for studying the role of innervation in cardiac function." Diss., The University of Arizona, 2004. http://hdl.handle.net/10150/280603.
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Cardiac activity of Drosophila melanogaster and Manduca sexta changes during metamorphosis. The larval heart has only anterograde contractions. Adult heart activity becomes a cyclic alternation of anterograde and retrograde contractions originated by putative anterograde and retrograde pacemakers. During development, the larval skeletal muscle motoneuron-1 in abdominal segments 7 and 8 becomes respecified to innervate the terminal cardiac chamber of adult Manduca and undergoes morphological and physiological reorganization. MNs-1 activate and sustain the anterograde pacemaker activity of the terminal chamber. The innervation of the adult abdominal heart of Drosophila melanogaster was studied to determine whether the adult heart receives neuronal input or whether its complex activity must be considered independent from the nervous system. The larval heart lacks innervation suggesting a myogenic cardiac impulse. At metamorphosis, neural processes grow onto the myocardium. A pair of glutamatergic transverse nerves innervates bilaterally each cardiac chamber. In addition, CCAP-immunoreactive fibers originating from peripheral, bipolar neurons (BpNs) fasciculate with the transverse nerve projections and terminate segmentally throughout the abdominal heart. To determine the role of this innervation in cardiac function, a novel optical technique based on the movement of GFP-labeled nerve terminals was developed to monitor heartbeat in intact preparations. Simultaneous monitoring of adjacent cardiac chambers revealed the direction of contractions and allowed correlation with volume changes. Intracellular recordings from the first abdominal cardiac chamber, the conical chamber, revealed pacemaker action potentials and the excitatory effect of local glutamate application. Bath-applied glutamate initiated retrograde contractions in semi-intact preparations. Similarly, electrical stimulation of the transverse nerve that serves the conical chamber caused a chronotropic effect and initiation of retrograde contractions. This effect is distinct from that of peripheral CCAP-immunoreactive neurons, which potentiate the anterograde beat. Cardiac reversal was evoked pharmacologically by sequentially applying CCAP and glutamate to the heart. The role of the neuropeptide, Crustacean Cardioactive Peptide (CCAP) in adult Drosophila melanogaster cardiac function was studied by RNA interference (RNAi) and targeted cell ablation. CCAP has a cardioacceleratory effect when it is applied in vitro. Lack of CCAP-innervation in CCAP knock-out flies altered one cardiac phase, the anterograde beat, without preventing the cyclic cardiac reversal.
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Nerelius, Charlotte. "Protein misfolding and amyloid formation : strategies for prevention /." Uppsala : Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, 2009. http://epsilon.slu.se/200941.pdf.
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Fluegel, Megan L. "Establishment of a Drosophila model of Niemann-Pick type C disease /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/5065.
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Baldwin, Katie. "A survey of axonal transport function and motor behaviour in Drosophila models of amyotrophic lateral sclerosis." Thesis, University of Sheffield, 2015. http://etheses.whiterose.ac.uk/12248/.
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Luheshi, Leila Mohamed. "Mutational analysis of the aggregation and toxicity of the amyloid beta peptide in a Drosophila model of Alzheimer's Disease." Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612965.
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Liu, Beinan. "Iron mediated amyloid beta toxicity and oxidative stress in a Drosophila melanogaster model of Alzheimer's disease." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608978.
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Stapper, Zeenna A. [Verfasser], and Bernd [Akademischer Betreuer] Bukau. "The role of redox homeostasis in Drosophila models of Aß aggregation / Zeenna A. Stapper ; Betreuer: Bernd Bukau." Heidelberg : Universitätsbibliothek Heidelberg, 2019. http://d-nb.info/1181106125/34.
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Lin, Ivy Carmen. "The Effects of Various Pharmacological Agents on the Sleep and Locomotor Activity of Drosophila Models of ALS." Thesis, The University of Arizona, 2013. http://hdl.handle.net/10150/297689.
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Amyotrophic Lateral Sclerosis (ALS) is a lethal, adult-onset, progressive neurodegenerative disease in which the degeneration and death of motor neurons results in muscle weakness and paralysis throughout the body, followed by death due to respiratory failure. As a RNA-binding protein, TDP-43 has been implicated as both a cause and marker of both familial (fALS) and sporadic (sALS) cases of the disease. Our laboratory has generated a Drosophila model of ALS based on human TDP-43, which allows us to study various aspects of the disease pathology in vivo, including sleep and locomotor activity. Because pharmacological treatment of ALS is currently limited to alleviating symptoms, with severely limited effects on the increase in survival period, studies of potential therapeutics would significantly contribute to the treatment of the disease. In identifying potential candidates, 4-aminoquinoline (AAQ) has shown potential in increasing survival of Drosophila TDP-43 mutants. Using the Trikinetics Drosophila Activity Monitoring system, we examine the ability of AAQ to ameliorate defects in sleep and locomotor activity in our model. Our data indicate that AAQ can decrease sleep fragmentation, suggesting that this small molecule has the potential to be developed as a drug therapy for ALS.
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Al, Zamal Faiyaz. "Relating the expression-based and sequence-based estimates of regulation in the gap gene system of Drosophila melanogaster." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112321.
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Quantitative analysis of Drosophila melanogaster gap gene expression data reveals valuable information about the nature and strengths of interactions in the gap gene network. We first explore different models for fitting the spatiotemporal gene expression data of Drosophila gap gene system and validate our results by computational analysis and comparison with the existing literature. A fundamental problem in systems biology is to associate these results with the inherent cause of gene regulation, namely the binding of the transcription factors (TF) to their respective binding sites. In order to relate these expression-based estimates of gap gene regulation with the sequence-based information of TF binding site composition, we also explore two related problems of (i) finding a set of regulatory weights that is proportional to the binding site occupancy matrix of the transcription factors in current literature and (ii) finding a set of position weight matrices of the TFs that produce a new binding site occupancy matrix showing a greater level of proportionality with our regulatory weights. Our solution to the first problem yielded a regulatory weight matrix incapable of explaining the true causes of gene expression profile despite its relative numerical accuracy in predicting the gene expressions. On the other hand, the second optimization problem could be solved up to a reasonable level of accuracy, but further analysis on the result demonstrated that this optimization problem may be under-constrained. We devise a simple regularization strategy that helps us to reduce the under-constrained nature of the problem.
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Yong, Li [Verfasser]. "Adrenergic signaling in the fruit fly Drosophila melanogaster : establishment and analysis of models for obesity and diabetes / Li Yong." Kiel : Universitätsbibliothek Kiel, 2018. http://d-nb.info/116965276X/34.
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Fetherson, Rebecca A. "An experimental and genomic approach to the regulation of alternative pre-mRNA splicing in Drosophila rnp-4f." Connect to this document online, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=miami1114713461.
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Thesis (M.S.)--Miami University, Dept. of Zoology, 2005.Title from first page of PDF document. Document formatted into pages; contains [1], ix, 75 p. : ill. Includes bibliographical references (p. 69-75).
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Bergkvist, Liza. "Amyloid-β and lysozyme proteotoxicity in Drosophila : Beneficial effects of lysozyme and serum amyloid P component in models of Alzheimer’s disease and lysozyme amyloidosis". Doctoral thesis, Linköpings universitet, Kemi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-137452.
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In the work presented this thesis, two different conditions that are classified as protein misfolding diseases: Alzheimer's disease and lysozyme amyloidosis and proteins that could have a beneficial effect in these diseases, have been studied using Drosophila melanogaster, commonly known as the fruit fly. The fruit fly has been used for over 100 years to study and better understand fundamental biological processes. Although the fruit fly, unlike humans, is an invertebrate, many of its central biological mechanisms are very similar to ours. The first transgenic flies were designed in the early 1980s, and since then, the fruit fly has been one of the most widely used model organisms in studies on the effects of over-expressed human proteins in a biological system; one can regard the fly as a living, biological test tube. For most proteins, it is necessary that they fold into a three-dimensional structure to function properly. But sometimes the folding goes wrong; this may be due to mutations that make the protein unstable and subject to misfolding. A misfolded protein molecule can then aggregate with other misfolded proteins. In Alzheimer's disease, which is the most common form of dementia, protein aggregates are present in the brains of patients. These aggregates are composed of the amyloid-β (Aβ) peptide, a small peptide of around 42 amino acids which is cleaved from the larger, membrane-bound, protein AβPP by two different enzymes, BACE1 and γ-secretase. In the first part of this thesis, two different fly models for Alzheimer’s disease were used: the Aβ fly model, which directly expresses the Aβ peptide, and the AβPP-BACE1 fly model, in which all the components necessary to produce the Aβ peptide in the fly are expressed in the fly central nervous system (CNS). The two different fly models were compared and the results show that a significantly smaller amount of the Aβ peptide is needed to achieve the same, or an even greater, toxic effect in the AβPP-BACE1 model compared to the Aβ model. In the second part of the thesis, these two fly models for Alzheimer’s disease were again used, but now to investigate whether lysozyme, a protein involved in our innate immune system, can counteract the toxic effect of Aβ generated in the fly models. And indeed, lysozyme is able to save the flies from Aβ-induced toxicity. Aβ and lysozyme were found to interact with each other in vivo. The second misfolding disease studied in this thesis is lysozyme amyloidosis. It is a rare, dominantly inherited amyloid disease in which mutant variants of lysozyme give rise to aggregates, weighing up to several kilograms, that accumulate around the kidneys and liver, eventually leading to organ failure. In the third part of this thesis, a fly model for lysozyme amyloidosis was used to study the effect of co-expressing the serum amyloid P component (SAP), a protein that is part of all protein aggregates found within this disease class. SAP is able to rescue the toxicity induced by expressing the mutant variant of lysozyme, F57I, in the fly's CNS. To further investigate how SAP was able to do this, double-expressing lysozyme flies, which exhibit stronger disease phenotypes than those of the single-expressing lysozyme flies previously studied, were used in the fourth part of this thesis. SAP was observed to reduce F57I toxicity and promote F57I to form aggregates with more distinct amyloid characteristics. In conclusion, the work included in this thesis demonstrates that: i) Aβ generated from AβPP processing in the fly CNS results in higher proteotoxicity compared with direct expression of Aβ from the transgene, ii) lysozyme can prevent Aβ proteotoxicity in Drosophila and could thus be a potential therapeutic molecule to treat Alzheimer’s disease and iii) in a Drosophila model of lysozyme amyloidosis, SAP can prevent toxicity from the disease-associated lysozyme variant F57I and promote formation of aggregated lysozyme morphotypes with amyloid properties; this is important to take into account when a reduced level of SAP is considered as a treatment strategy for lysozyme amyloidosis.
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Dureau, Maxime. "Characterization and simulation of the mechanical forces that control the process of Dorsal Closure during Drosophila melanogaster embryogenesis." Thesis, Lyon, École normale supérieure, 2015. http://www.theses.fr/2015ENSL0999/document.
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Le travail de thèse présenté ici vise à caractériser et simuler les forces mécaniques impliquées dans le processus de fermeture dorsale chez l’organisme Drosophila melanogaster. Ce processus participe à l’acquisition par l’embryon de sa forme finale. Ainsi, l’objectif du travail présenté ici est d’approfondir nos connaissances sur la mécanique des tissus,ainsi que sur leur rôle dans l’embryogenèse.La fermeture dorsale est un processus similaire à la cicatrisation, dans lequel la fermeture du trou dorsal est réalisée par l'amnioséreuse, qui couvre le trou dorsal, et la rangée la plus dorsale des cellules de l'épiderme: les leading edge cells.Une partie du travail présenté ici étudie aussi les mouvements des cellules du leading edge,dans le but de comprendre l’effet du câble d’actine sur la dynamique de la fermeture dorsale.Un algorithme permettant de détecter les contours des cellules, leur position ainsi que celle de leurs jonctions multiples a été développé, ainsi qu'un interface utilisateur.Différents modèles dynamiques ont ensuite été construits, prenant en compte différents comportements mécaniques, selon l’approche lagrangienne. Les systèmes d’équations ont été résolus numériquement, et leurs prédictions comparées aux données biologiques selon l’approche des moindres carrés. Les résultats ont été validés par le test de la fonction d’auto corrélation.Les résultats présentés dans cette thèse nous permettent de mieux comprendre les processus mécaniques impliqués dans les oscillations des cellules de l’amnioséreuse. Ils nous donnent aussi des indices sur leurs caractéristiques biologiques. Ils nous permettent enfin de mieux appréhender le rôle du cabled’actine dans ce processusThe work presented here aims at characterizing and simulating the mechanical forces involved in the process of Dorsal Closure in the organism Drosophila melanogaster, an embryonic process. In particular, Dorsal Closure participates in the acquisition of the final form of the embryo. Therefore, the work presented here aims at fathoming our knowledge on tissues mechanics, as well as their role in the acquisition of shape. The tissues involved in Dorsal Closure are the epidermis and the amnioserosa. At this stage of development, the epidermis surrounds almost all the embryo. Nevertheless, the amnioserosa still covers a large area of the dorsal side called dorsal hole. Hence, Dorsal Closure aims at shutting this hole and joining the lateral sides of the epidermis, in a process similar to wound healing. In order to fuse the two sides of the epidermis on the dorsal line, the epidermis must be drawn dorsalward. This movement is driven by the amnioserosa on the one hand, and by the dorsalmost row of the epidermis (called Leading Edge cells) on the other hand. The latter first form a transcellular Actin Cable around the dorsal hole. The cable, contracting, will reduce the area of the dorsal hole, covered by the amnioserosa. Second, the Leading Edge cells emit protrusions that will attach to the opposite Leading Edge and drag it toward themselves, untill the two sides of the epidermis fuse. These protrusions have a limited range, hence the dragging and fusion only take place at the ends of the dorsal hole (called canthi), where the distance between the two Leading Edges is small enough. The Amnioserosa also drags the epidermis toward the dorsal line. Its cells produce a contractile network. Interstingly, Amnioserosa cells see the area of their top side (apical side) vary in a periodic way. Although these variations have been widely studied, their role in Dorsal Closure remains unknown. This PhD aims at improving our knowledge of the mechanical concepts involved in these oscillations, and to build a physical model representing these movements. The work presented here also studies the movements of the Leading Edge cells, in order to understand the effect of the Actin Cableon the dynamics of Dorsal Closure. In order to study the cells movements and the role of the tissues involved in Dorsal Closure, an algorithm was developped, allowing to detect the cells edges, their position, as well as those of their vertices (multiple junction between three or four cells) and to track them over time. A user interface was also developped, in order to facilitate the adjustment of the parameters allowing the detection, as well as the correction of possible errors. Various dynamical models were then built following the lagrangian approach. The systems of equations deriving from the Euler-Lagrange equations were numerically solved, and their predictions compared to the biological data extracted thanks to the algorithm presented earlier, following the least square approach. The model validation was performed thanks to the autocorrelation function test. Finally, the Leading Edge dynamics was studied characterising the cellular movements at the interface between the epidermis and the amnioserosa. Wild type embryos dynamics were compared to those of mutated embryos showing specific defects in the Actin Cable formation. The results presented in this manuscript allow a better understanding of the processes involved in in Amnioserosa cells oscicllations. They also give clues on their biological characteristics. Finally, they assess the role of the actin cable in this process similar to wound healing
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Haye, Alexandre. "Modélisation de l'évolution temporelle de l'expression des gènes sur la base de données de puces à ADN: application à la drosophile." Doctoral thesis, Universite Libre de Bruxelles, 2011. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209904.
Повний текст джерелаАнотація:
Cette thèse de doctorat s’inscrit dans le développement et l’utilisation de méthodes mathématiques et informatiques qui exploitent les données temporelles d’expression des gènes issues de puces à ADN afin de rationaliser et de modéliser les réseaux de régulation génique. Dans cette optique, nous nous sommes principalement intéressés aux données d’expression des gènes de la drosophile (Drosophila melanogaster) pendant son développement, du stade embryonnaire au stade adulte. Nous avons également étudié des données concernant le développement d’autres eucaryotes supérieurs, la réponse d’une bactérie soumises à différents stress et le cycle cellulaire d’une levure. Ce travail a été réalisé selon trois volets principaux :la détection des stades de développement et des perturbations, les classifications de profils d’expression et la modélisation de réseaux de régulation.Premièrement, l’observation des données d’expression utilisées nous a conduits à approfondir l’étude des phénomènes survenant lors des changements de stades de développement de la drosophile. Dans ce but, deux méthodes de détection automatique de ces changements ont été développées et appliquées aux données temporelles disponibles sur le développement d’eucaryotes supérieurs. Elles ont également été appliquées à des données temporelles relatives à des perturbations externes de bactéries. Cette étude à montré qu’une formulation mathématique simple permettait de retrouver les instants expérimentaux où une perturbation ou un changement de stade de développement est observé, à partir uniquement des profils d’expression. Par ailleurs, la réponse à une perturbation externe s’avère non distinguable d’une succession de stades de développement, sur la base des seuls profils temporels d’expression.
Deuxièmement, en raison des dimensions du problème constitué par les données d’expression de plusieurs milliers de gènes et de l’impossibilité de distinguer le rôle dans la régulation des gènes qui présentent des profils d’expression similaires, il s’est avéré nécessaire de classifier les gènes selon leurs profils d’expression. En nous basant sur les résultats obtenus lors de la détection des stades de développement, la démarche suivie est de regrouper les gènes qui présentent des profils temporels d’expression aux comportements similaires non seulement au cours de la série temporelle complète, mais également dans chacun des stades de développement. Dans cette optique, trois distances ont été proposées et utilisées dans une classification hiérarchique des données d’expression de la drosophile.
Troisièmement, des structures de modèles linéaires et non linéaires ainsi que des méthodes d’estimation et de réduction paramétriques ont été développées et utilisées pour reproduire les données d’expression du développement de la drosophile. Les résultats de ce travail ont montré qu’avec une structure de modèle linéaire simple, la reproduction des profils expérimentaux était excellente et que, dans ce cas, le réseau de régulation génique de la drosophile pouvait se contenter d’une faible connectivité (en moyenne 3 connexions par classe de gènes) et ce, sans hypothèse a priori. Toutefois, les modèles linéaires ont ensuite sérieusement été remis en question par des analyses de robustesse aux perturbations paramétriques et de stabilité des profils après extrapolation dans le temps. Dès lors, quatre structures de modèles non linéaires et cinq méthodes de réduction paramétrique ont été proposées et utilisées pour concilier les critères de reproduction des données, de robustesse et de stabilité des réseaux identifiés. En outre, ces méthodes de modélisation ont été appliquées à un sous-ensemble de 20 gènes impliqués dans le développement musculaire de la drosophile et pour lesquels 36 interactions ont été validées expérimentalement, ainsi qu’à des profils synthétiques bruités. Nous avons pu constater que plus de la moitié des connexions et non-connexions sont retrouvées par trois modèles non linéaires. Les résultats de cette étude ont permis d’éliminer certaines structures de modèle et méthodes de réduction et ont mis en lumière plusieurs directions futures à suivre dans la démarche de modélisation des réseaux de régulation génique.
Doctorat en Sciences de l'ingénieur
info:eu-repo/semantics/nonPublished
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Smith, Aaron. "Vertex model approaches to epithelial tissues in developmental systems." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:4d19f232-764c-4e27-bca9-d2ede0ec2db9.
Повний текст джерелаАнотація:
The purpose of this thesis is to develop a vertex model framework that can be used to perform computational experiments related to the dynamics of epithelial tissues in developmental systems. We focus on three example systems: the Drosophila wing imaginal disc, the Drosophila epidermis and the visceral endoderm of the mouse embryo. Within these systems, key questions pertaining to size-control mechanisms and coordination of cell migration remain unanswered and are amenable to computational testing. The vertex model presented here builds upon existing frameworks in three key ways. Firstly, we include novel force terms, representing, for example, the reaction of a cell to being compressed and its shape becoming distorted during a highly dynamic process such as cell migration. Secondly, we incorporate a model of diffusing morphogenetic growth factors within the vertex framework, using an arbitrary Lagrangian-Eulerian formulation of the diffusion equation and solving with the finite-element method (FEM). Finally, we implement the vertex model on the surface of an ellipsoid, in order to simulate cell migration in the mouse embryo. Throughout this thesis, we validate our model by running simple simulations. We demonstrate convergence properties of the FEM scheme and discuss how the time taken to solve the system scales with tissue size. The model is applied to biological systems and its utility demonstrated in several contexts. We show that when growth is dependent on morphogen concentration in the Drosophila wing disc, proliferation occurs preferentially in regions of high concentration. In the Drosophila epidermis, we show that a recently proposed mechanism of compartment size-control, in which a growth-factor is released in limited amounts, is viable. Finally, we examine the phenomenon of rosettes in the mouse embryo, which occur when five or more cells meet at a common vertex. We show, by running simulations both with and without rosettes, that they are crucial facilitators of ordered migration, and are thus critical in the patterning of the early embryo.
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Niehus, Sebastian. "Développement d’un modèle d’étude génétique des relations hôtes- parasites entre un parasite intracellulaire obligatoire, la microsporidie Tubulinosema ratisbonensis et l’organisme modèle Drosophila melanogaster." Thesis, Strasbourg, 2012. http://www.theses.fr/2012STRAJ137.
Повний текст джерелаАнотація:
Plus de 150 années de recherches sur les Microsporidies ont conduit à une connaissance relativement basique de divers aspect de leur biologie. Malgré cela, peut d’informations existent concernant la génétique et les mécanismes moléculaire des interactions hôte-pathogène qui gouvernent les infections aux Microsporidies.Dans un premier temps, je décris comment détecter, traiter et éradiquer les infections microsporidiales avec Tubulinosema ratisbonensis dans des lignées de Drosophila melanogaster. Jusqu’à présent, les connaissances concernant les défenses de l’hôte chez la drosophile contre les parasites intracellulaire obligatoires restent incomplète due au manque d’un bon modèle d’infection. De ce fait, j’ai développé des modèles d’infection de D. melanogaster par la microsporidie T.ratisbonensis, à la fois en culture cellulaire et drosophiles adultes. Mes travaux sur le modèle d’infection cellulaire englobent des approchent en transcriptomique et métabolomique qui analysent les deux cotées de cette relation hôte-pathogène. En fin, je présente les fonctions biologiques des glycosylphosphatidyl inositoles de Toxoplasma gondiiMore than 150 years of Microsporidia research led to a basic understanding of many aspects of microsporidial biology, yet little is known about the genetic basis and molecular mechanisms of the intimate host-parasite relationship that govern Microsporidia infections.Here, I first report on the detection, prophylaxis, and eradication measures against microsporidial infestations with Tubulinosema ratisbonensis, infecting cultures of Drosophila melanogaster. To date,knowledge about Drosophila host defense against obligate intracellular parasites remained incomplete for lack of good infection models.To this end, I have developed infection models of Drosophila by the microsporidian T. ratisbonensis,both in cell lines and in adults. The work on the cellular infection model encompasses transcriptomics and metabolomics approaches, which aim to attempt both sides of the host-pathogen equation. Finally, I report on the biological roles of glycosylphosphatidyl inositols of Toxoplasma gondii
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Plantié, Émilie. "Utilisation d'un modèle drosophile pour l'identification de marqueurs moléculaires responsables des symptômes musculaires et cardiaques de la maladie de Steinert." Thesis, Clermont-Ferrand 1, 2016. http://www.theses.fr/2016CLF1MM19/document.
Повний текст джерелаАнотація:
La maladie de Steinert ou dystrophie myotonique de type 1 (DM1), dystrophie musculaire la plus commune chez l’adulte, est causée par l’expansion instable de triplets CTG dans la région 3’ non traduite du gène DMPK (Dystrophia Myotonica Protein Kinase). Cette maladie multisystémique, affectant principalement les muscles squelettiques et le cœur, est liée à l’épissage. En effet, les CUG exp forment des structures secondaires dans le noyau capables de séquestrer la protéine MBNL1, facteur d’épissage alternatif. En parallèle, un autre facteur d’épissage alternatif, CELF1 est stabilisé. La dérégulation de la balance entre ces deux protéines cause des défauts d’épissage, responsables de certains symptômes de la maladie, comme la myotonie, des défauts de conduction cardiaque et une résistance à l’insuline, causés respectivement par l’épissage aberrant du canal chlorure Clcn1, du canal sodique SCN5A et du récepteur à l’insuline IR. De plus, des dérégulations indépendantes de l’épissage sont aussi mises en jeu dans la DM1 mais leur responsabilité dans l’apparition des symptômes de la maladie reste à identifier. Pour identifier des dérégulations transcriptionnelles indépendantes de l’épissage mais liées à la progression et à la sévérité des symptômes, nous avons généré de nouveaux modèles drosophile de la DM1 avec un nombre croissant de répétitions CTG. Ces modèles étudiées au stade larvaire récapitulent les caractéristiques majeures de la DM1 : la formation de foci et une hypercontractilité musculaire. De plus, nous avons identifié dans ce modèle des dérégulations géniques indépendantes de l’épissage mais dépendantes du nombre de répétitions CTG. Notamment, une atténuation de Gbe1, codant pour une enzyme de branchement du glycogène pourrait participer aux phénotypes musculaires. Afin d’étudier les symptômes cardiaques de la maladie qui touchent 80% des patients et représentent la deuxième cause de mortalité, nous avons utilisé le modèle DM1 de drosophile développé dans notre équipe, et réalisé des analyses physiologiques cardiaques sur des mouches adultes qui expriment 960 CTG dans le cœur (Hand>DM1 960 ), un ARNi pour Mbl, l’orthologue de MBNL1, ou qui surexpriment l’orthologue de CELF1, Bru-3. Ces trois modèles DM1 reproduisent les symptômes cardiaques majeurs observés chez les patients comme des défauts de conduction, de l’arythmie (fibrillation) ou encore une cardiomyopathie dilatée. Afin d’identifier des dérégulations géniques susceptibles d’être responsables de ces défauts, nous avons réalisé une analyse transcriptomique par séquençage ARN après collection de l’ARN spécifique du cœur par la technique du TU-tagging. Les gènes dérégulés identifiés dans ces contextes ont été classés en fonction de leur conservation et du niveau de dérégulation. Parmi eux, la surexpression dans le cœur adulte de Straightjacket (Stj), l’orthologue de CACNA2D4 qui code pour une sous-unité d’un canal calcique voltage- dépendant, cause des défauts de conduction et de la fibrillation, mimant ce qui a été observé en contexte DM1 960 et gain de fonction pour Bru-3. Dans l’avenir, nous aimerions confirmer son implication dans la physiologie cardiaque et en particulier dans la DM1 en analysant son expression chez les patients présentant des défauts cardiaques similairesThe most common muscular dystrophy found in adults, Steinert disease or Myotonic Dystrophy Type 1 (DM1) is caused by an unstable CTG repeat expansion in the 3’ untranslated region of the Dystrophia Myotonica Protein Kinase (DMPK) gene. This multisystemic disease, affecting particularly skeletal muscles and the heart, is called a spliceopathy because it involves the sequestration of the MBNL1 splicing factor by the expanded CUG-carrying transcripts and the stabilization of the CELF1 splicing factor. The misbalance of these two factors is responsible for splicing defects that cause most of the disease symptoms, like myotonia, conduction defects and arrhythmia but also insulin resistance, respectively associated to missplicing of Clcn1, SCN5A and IR. Moreover, DM1 toxicity is also associated to splice-independent deregulations but their link to disease symptoms remain poorly understood. To identify transcriptional deregulations independent of splicing and associated to disease progression and severity, we generated new DM1 Drosophila models with increasing number of CTG repeats. These larval models recapitulated the main DM1 muscular symptoms such as hypercontractility and foci formation and allowed us identifying gene deregulations independent of splicing. Among them, Gbe1 coding for a glycan branching enzyme is attenuated in the DM1 context in a CTG-repeat dependant manner and could participate in the severity of muscle phenotypes. To better understand the causes of cardiac symptoms that represent the second cause of death and affecting 80% of DM1 patients, we took advantage of our DM1 inducible Drosophila model and performed phenotypic analyses on the heart of adult flies expressing: 960 CTG specifically in the heart (Hand>DM1 960 ), a RNAi for the Drosophila MBNL1 orthologue (Muscleblind, Mbl) or overexpressing the CELF1 orthologue (Bruno-3, Bru3). These DM1 adult models display conduction abnormalities, arrhythmicity (fibrillation) and dilated cardiomyopathy (DCM). Thus, these three pathogenic contexts recapitulated collectively the main DM1 cardiac symptoms and prompted us to perform transcriptional profiling to identify symptom’s-associated gene deregulations. To identify new molecular actors responsible for the DM1 associated heart defects, we performed cardiac cell-specific transcriptional analyses by RNA-sequencing, using TU-tagging technique. Then, we selected deregulated candidate genes that could be linked to the particular observed phenotypes and ranked depending on their conservation and deregulation level. Among them, increased expression of Straightjacket (Stj), the CACNA2D4 orthologue, encoding a subunit of voltage- dependent calcium channel results in fibrillation and conduction defects, thus mimicking cardiac symptoms found in DM1 960 and Bru-3 gain of function contexts in which it was up- regulated. Whether identified candidates are deregulated in DM1 patients displaying cardiac abnormalities remains to be tested
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Badji, Aisha. "A PCOS-like Drosophila Melanogaster model." Thesis, Högskolan i Skövde, Institutionen för hälsa och lärande, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-17845.
Повний текст джерелаАнотація:
Polycystic ovary syndrome (PCOS) is a female endocrine disorder defined by high androgen levels and presence of polycystic ovaries. PCOS is characterized by menstrual irregularities, anovulation, infertility, hyperandrogenism, insulin resistance, abdominal obesity, chronic inflammation and increased hair growth. The diagnosis is based on 2003/2004 Rotterdam criteria, which is based on the presence of the following phenotypes: anovulation, clinical and biochemical marks of hyperandrogenism and polycystic ovarian morphology. Theoretical causes could be genetical, environmental or maternal imprinting. Drosophila Melanogaster, a model used broadly in disease research, could bear promising insights to this syndrome. Besides having a lifecycle characterized by a 12 days metamorphism, these species of flies have the ecdysone (steroid) hormone, similar to the human testosterone and the body systems similar to those of the human body. This laboratory work involved the development of a PCOS-like drosophila fly model through exposure to 10mg/ml of testosterone after 24 hours of starvation. Data collection comprised measurements of weight and length, anovulation, triglyceride quantification and RT-qPCR for quantification of inflammatory and PCOS-related genes. Results showed significant differences in response to physical stress among the four groups of flies. Variation in weight and length values, as well as in fecundity, triglyceride assay and relative expression levels were also observed. Although the expression levels of inflammatory and PCOS- related genes were not significantly affected, homeostasis was clearly affected by metabolic disturbances. These observations lead to the conclusion that further experiments should be done in order to establish a more comprehensive definition of the syndrome.
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Sarkar, Ankita. "Drosophila Eye Model to Study Neurodegeneration." University of Dayton / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=dayton1537311159395439.
Повний текст джерела
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Gupta-Bosch, Tripti. "Deciphering intrinsic and extrinsic machinery underlying collective glia migration using Drosophila as a model organism." Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAJ009/document.
Повний текст джерелаАнотація:
La capacité remarquable des neurones et des cellules gliales à migrer collectivement sur de longues distances assure l’architecture finale du cerveau. Ce processus est extrêmement dynamique et dépend non seulement de l’interaction entre les cellules mais aussi de la présence de facteurs de transcriptions spécifiques au sein de la cellule migrante. Les protéines d’adhésion comme les cadhérines et les chimioattractants/chimiorépulsifs sont connus pour réguler et guider la migration. Si le mode d’action de ces molécules a été extensivement étudié, les cascades de signalisation qui déclenchent le chimiotropisme sont loin d’être élucidées. Au cours de mon doctorat, j’ai analysé la régulation et le rôle d’un récepteur des chimioattractant au cours de la migration de la glie. Pour ceci j’ai utilisé le modèle du développement de la chaine gliale dans l’aile de la drosophile qui représente un outil de choix pour étudier les mécanismes moléculaires régulant la migration collectiveThe remarkable ability of neurons and glia to undergo long distance and collective migration ensures the final architecture and function of the brain. This is an extremely dynamic process that not only depends on cell interactions, but also on the presence of specific transcription factors in the migrating cells. Adhesion molecules such as classic cadherins and chemoattractants/repellants are known to regulate directional migration, however, how are these pathways regulated is largely unknown. While the role of these molecules controlling cell interactions has been extensively investigated, the signaling cascades that trigger chemotropism are not understood. During the course of my PhD I have analyzed the role of an adhesion molecule and the impact of a chemoattractant receptor regulated by an early transcription factor in the process. The glial chain in a developing Drosophila wing provides an excellent tool to study the molecular pathway underlying collective migration
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Voght, Stephen P. "Establishment of a Drosophila model of intestinal sterol absorption and trafficking /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/10303.
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Martorell, Aleman Òscar. "Modelling colorectal cancer in Drosophila = Establiment d'un model de càncer colorectal a Drosophila." Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/145376.
Повний текст джерелаАнотація:
During last decades many researchers have tried to elucidate the different causes of tumour initiation and progression. For this purpose, multiple animal models have been developed to understand the cellular and molecular processes that underlie the cancer disease. The main aim of this thesis has been the generation and characterization of a colorectal cancer model (CRC) in Drosophila melanogaster. With the generation of a CRC in Drosophila, we sought to determine which are those key genes essential during colorectal tumorigenesis. Colorectal cancer (CRC) is one of the most common cancers in the developed countries. The term CRC includes all those malignant lesions that affect the large intestine, the rectum and the appendix. Most of the cases of CRC are sporadic and occur by the accumulation of somatic mutations during the life of the patient. In 1990, Fearon and Vogelstein presented a genetic model to explain how the CRC arise from pre-malign lesions by the accumulation of a set of mutations that would increase progressively the malignancy of the tumour cells (E. Fearon & Vogelstein, 1990). More than 90% of CRC cases have activating mutations in components of the Wnt pathway, and its activation is considered one of the first events in CRC progression. The second more altered signalling pathway is the RTK-RAS pathway, with activating mutations in around 60% of the cases. Mutations in TP53 (64%), PI3K (50%) or TGF-β (27%) pathways are also considered main events for CRC progression (Network, 2012). The generation of a CRC in Drosophila has been possible by the alteration of two main genes involved in human CRC, the Wnt pathway negative regulator Apc and the oncogene Ras. Flies bearing clones mutant for Apc and overexpressing an oncogenic form of Ras (Apc-Ras) develop tumour-like overgrowths in the most anterior part of the adult midgut. These clones show many tumoural characteristics such as high cell proliferation, loss of cell polarity, severe dedifferentiation or expression of migratory markers. In addition, the analysis of the Apc-Ras transcriptome has allowed us to identify hundreds of putative genes involved in tumour progression as well as to confirm the tumour-like behaviour of the Apc-Ras cells. At transcriptional level, Apc-Ras cells present differential expression of many genes encoding signalling proteins and transcription factors that could be crucial for clone development. Interestingly, a RNAi screening has confirmed the essential contribution of some of these genes. In particular, this work has focused in the implication of the TGF-β pathway in Apc-Ras clone progression. TGF-β has emerged as a powerful Apc-Ras clone suppressor and its inactivation is critical for the progression of Apc-Ras clones. Moreover, we have identified the transcription factor Mirror as an essential transcriptional repressor of many of the components of the TGF-β pathway during Apc-Ras progression. Finally, these results have been partially confirmed in in vitro human cell cultures indicating a putative role of IRX proteins (the human homologues of Mirror) in human CRC progression.
This work opens the possibility to study the real implication of many putative genes in an easy genetic model and strongly supports the use of Drosophila as a good animal model system to study molecular and cell cancer biology.Un dels càncers més comuns als països desenvolupats és el càncer colorectal (CRC). El terme CRC inclou totes aquelles lesions tumorals que ocorren a l’intestí gros, el recte i l’apèndix. Aquests càncers ocorren per l’acumulació de mutacions al llarg de la vida del pacient. Més d’un 90% de CRC tenen alteracions a la via de Wnt i la seva activació és considerada un dels primers esdeveniments en la progressió del CRC. La segona via de senyalització més alterada durant la progressió del CRC és la via de RTK-RAS amb alteracions activadores de la via presents en un 60% dels casos de CRC (E. R. Fearon, 2011). L'objectiu principal d'aquesta tesi ha estat establir i caracteritzar un model de CRC a Drosòfila per comprendre millor els processos tumorals i alhora identificar nous gens implicats en la progressió del CRC. Per a generar el model de càncer colorectal a l’intestí mig adult vam induir clons mutants pel gen Apc i sobreexpresant la forma activada de Ras, activant així de forma simultània la via de Wnt i EGFR en les mateixes cèl•lules de l’intestí adult de Drosophila. (clons Apc-Ras). Els clons Apc-Ras mostren característiques tumorals tals com: falta de diferenciació, hiperproliferació, falta de polaritat cel•lular. A més a més els clons Apc-Ras mostren un silenciament transcripcional de la via de senyalització de Dpp. Aquest silenciament és essencial per a la progressió dels clons Apc-Ras degut al paper citostàtic de la via de senyalització Dpp. A més a més aquest treball també ha identificat el factor repressor responsable del silenciament de la via de Dpp, el factor de transcripció Mirror. Mitjançant l’expressió de Mirror les cèl•lules Apc-Ras reprimeixen transcripcionalment diversos components de la via de Dpp i evadeixen així el rol citostàtic d’aquesta via. Finalment aquest treball demostra que les proteïnes IRO (homòlogues a Mirror en humans) podrien exercir un rol de similar a Mirror, reduint la resposta a TGF-β/Dpp per part de les cèl•lules tumorals durant la progressió del CRC
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Picchio, Lucie. "Mise en place, caractérisation phénotypique et transcriptomique d'un modèle de Drosophilie de la Dystrophie Myotonique de type 1." Thesis, Clermont-Ferrand 1, 2013. http://www.theses.fr/2013CLF1MM15/document.
Повний текст джерелаАнотація:
La dystrophie myotonique de type 1 (DM1) ou maladie de Steinert est la maladie génétique neuromusculaire la plus commune avec une incidence de 1/8000 à travers le monde. Cette maladie multisystémique touche particulièrement les muscles squelettiques (myotonie, faiblesse et perte musculaires) et le coeur qui présente des symptômes variés comme des troubles de la conduction et des arythmies. La DM1 est causée par une expansion instable de répétitions CTG dans la région 3’ non traduite du gène DMPK. Les individus sains possèdent entre 5 et 37 répétitions CTG tandis que les patients DM1 portent entre 50 et plusieurs milliers de répétitions. Il est bien établi que les expansions de répétitions non codantes forment des foci dans les noyaux musculaires où elles séquestrent le facteur d'épissage MBNL1. Toutefois, l'implication de la stabilisation et l'accumulation de CUGBP1 hyperphosphorylé par la PKC dans la maladie est un sujet controversé dans la communauté DM1. Dernièrement, en plus de la rupture de l'équilibre entre MBNL1/CUGBP1, plusieurs mécanismes ont été mis en cause dans la pathogenèse de la DM1. Parmi eux, l'expression perturbée de facteurs de transcription, la maturation altérée de miARNs, l'activation de kinases... chacune de ces altérations menant au final à une perturbation du transcriptome. Afin d'étudier l'effet de la toxicité des répétitions sur les phénotypes et lestranscriptomes, nous avons généré trois lignées de Drosophile inductibles et site-spécifiques exprimant 240, 600 et 960 répétitions de triplets. Nous avons travaillé en parallèle sur une lignée atténuée pour mbl (orthologue de MBNL1) et deux lignées gain de fonction bru -3 (orthologue de CUGBP1). Exprimées dans les muscles somatiques, les répétitions CTG conduisent à une mobilité réduite, le fractionnement des fibres musculaires, une réduction de leur taille et une altération du processus de fusion des myoblastes de manière dépendante de Mbl et Bru-3. En outre, l'expression des répétitions cause une hypercontraction musculaire dépendante de Mbl et due à un mauvais épissage de dSERCA. L'analyse transcriptionnelle comparative réalisée sur les muscles larvaires des différentes conditions pathologiques montre que l'atténuation de mbl reproduit 70-82% des dérégulations transcriptomiques des larves DM1 alors que le gain de fonction bru-3 représente 32-53% des altérations transcriptomiques des lignées DM1. Ainsi Mbl est un facteur clé des dérégulations observées dans les muscles somatiques des lignées DM1. Au contraire, les analyses physiologiques effectuées sur les coeurs adultes suggèrent que Bru-3 est un facteur clé dans la mise en place des phénotypes cardiaques. En effet, d'une part, l'atténuation de mbl dans le coeur cause une cardiomyopathie dilatée, un symptôme rarement diagnostiqué chez les patients. D'autre part, les lignées gain de fonction bru-3 et DM1 présentent de la fibrillation qui évolue avec l'âge ou la taille des répétitions vers un phénotype qui rappelle l'insuffisance cardiaque chez les patientsMyotonic Dystrophy Type 1 (DM1) or Steinert's disease is the most common genetic neuromuscular disorder affecting 1 out of 8000 people worldwide. This multisystemic disease affects particularly the skeletal muscles (myotonia, muscle weakness and wasting) and the heart, which can exhibit various symptoms like conduction disturbances and arrhythmia (auricular fibrillation and flutter). DM1 is caused by an unstable CTG repeat expansion in the 3' non-translated region of the DMPK gene. In healthy individuals, the number of CTG repeats ranges from 5 to 37 whereas DM1 patients carry from 50 to thousands repeats. It is well established that when expanded non-coding repeats aggregate into foci within muscle nuclei and sequester the MBNL1 splicing factor. However, the involvement of the stabilization and accumulation of CUGBP1 following PKC hyper-phosphorylation in the disease is a controversial matter in the DM1 community. Lately, in addition to the disruption of the balance between MBNL1/CUGBP1, several mechanisms were identified as part of the DM1 pathogenesis. Among them, transcription factors perturbations, altered maturation of miRNA, kinases activation… each of them leading eventually to transcriptomic alterations. In order to investigate the effect of toxic repeat expression on phenotypic and transcriptomic alterations, we generated three inducible site-specific Drosophila lines expressing 240, 600 and 960 triplet repeats. We worked in parallel on a mbl (MBNL1 orthologue) knocked-down line and two bru-3 (CUGBP1 orthologue) gain of function lines. When expressed in somatic muscles, CTG repeats lead to altered motility, fiber splitting, reduced fiber size and affected myoblast fusion process in a Mbl and Bru-3 dependent manner. In addition, toxic repeats cause fiber hyper-contraction in a Mbldependentmanner due to dSERCA mis-splicing. Comparative transcriptional profiling performed on larval muscles of different conditions show that mbl attenuation reproduces 70-82% of DM1 transcriptomic deregulations whereas bru-3 gain of function represents 32-53% of transcritomic alterations. Thus Mbl appears as a key factor of transcripts deregulations observed in DM1 muscles. On the contrary, physiologic analyses performed on adult hearts suggest that Bru-3 is a key factor for cardiac phenotypes. Indeed, on one hand, mbl attenuated flies display dilated cardiomyopathy, a symptom barely diagnosed in patients. On the other hand, bru-3 gain of function line and DM1 lines display fibrillation, which evolves withage or repeat size into a phenotype reminiscent of heart insufficiency in patients
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Brunk, Kathrin. "A Drosophila model for MCPH1 primary microephaly." Thesis, University of Leeds, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.530842.
Повний текст джерела
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Pokrzywa, Malgorzata. "A Drosophila Disease-Model for Transthyretin-associated Amyloidosis." Doctoral thesis, Umeå : Umeå University, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1677.
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Lee, Wyan-Ching Mimi. "Characterization of a Drosophila model of Huntington's disease." Thesis, Massachusetts Institute of Technology, 2006. http://hdl.handle.net/1721.1/34571.
Повний текст джерелаАнотація:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2006.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Includes bibliographical references.
Huntington's disease (HD) is an autosomal dominant neurological disorder caused by a polyglutamine (polyQ) repeat expansion in the huntingtin (Htt) protein. The disease is characterized by neurodegeneration and formation of neuronal intracellular inclusions primarily in the striatum and cortex, leading to personality changes, motor impairment, and dementia. To date, the molecular mechanisms that underlie the neurodegenerative process remain to be defined. Development of transgenic Drosophila HD models may facilitate dissection of molecular and cellular pathways that lead to disease pathology and suggest potential strategies for treatment. To explore mutant Htt-mediated mechanisms of neuronal dysfunction, we generated transgenic Drosophila that express the first 548 amino acids of the human Htt gene with either a pathogenic polyglutamine tract of 128 repeats (Htt-Q128) or a nonpathogenic tract of 0 repeats (Htt-QO). Characterization of these transgenic lines indicates formation of cytoplasmic and neuritic Htt aggregates in our Drosophila HD model that sequester other non-nuclear polyQ-containing proteins and block axonal transport.
(cont.) To further explore axonal transport defects in Huntington's disease, we generated Drosophila transgenic strains expressing 588 aa or exon 1 N-terminal fragments of human huntingtin encoding pathogenic (HttQ138) or nonpathogenic (HttQ15) proteins tagged with mRFP and/or eGFP. These transgenic lines enable in vivo imaging of Htt aggregation and trafficking in live Drosophila, providing a unique resource for tracking Htt in real time. Our findings indicate that expression of mutant Htt may impair axonal transport through both aggregate-dependent and -independent means. Finally, to assay the therapeutic effect of expression of an intracellular antibody (intrabody) against Htt, we generated double transgenic lines coexpressing pathogenic Htt (mRFP-HttQ138) with the V12.3 intrabody. Intrabody expression caused suppression of aggregation in both neuronal and non-neuronal cell types, but failed to rescue mutant Htt-mediated cellular dysfunction. In summary, our Drosophila HD model provides an ideal in vivo system for examination of mutant Htt-mediated cellular defects, particularly impairment of axonal transport, and may facilitate rapid development and validation of potential treatments for Huntington's disease.
b y Wyan-Ching Mimi Lee.
Ph.D.
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Pratt, Metta. "Drosophila melanogaster as a model to study ciliogenesis." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:09fa66c3-0be0-424e-a02d-8c72377ebc91.
Повний текст джерелаАнотація:
Cilia are microtubule-based extensions of the cell membrane that extend from a mature centriole. Primary (non-motile) cilia are present on most human cells and have important roles in signalling pathways. At the base of the cilium is a selective barrier known as the transition zone (TZ). Defects in the TZ are associated with human congenital diseases such as Meckel-Gruber syndrome (MKS) and Nephronophthisis (NPHP). The TZ is formed by three protein complexes, the MKS, NPHP and Cep290 modules, although the fruit fly Drosophila melanogaster appears to lack the core components of the NPHP module. Results presented in this thesis shows that MKS proteins are spatially separated from Cep290 at the TZ in Drosophila spermatocyte cilia. The TZ of the spermatocyte cilia is perturbed in flies mutant for MKS1 (MKS1Δ1) and fails to recruit key TZ proteins, although Cep290 and Chibby are recruited normally. Male fertility, however, is unaffected. Similarly, while there are substantial abnormalities in microtubule and membrane organisation in developing MKS1Δ1 mutant cilia, defects in mature MKS1Δ1 mutant cilia are limited to subtle changes in IFT and a membrane surrounded volume within the cilium. The function of sensory neurons is not negatively affected by the MKS1Δ1 mutation. Evidently, given enough developmental time, ciliary defects can be largely rescued in flies and the localisation of MKS module proteins to the cilia or flagella is not essential for viability or fertility in Drosophila.