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1
Pileyre, Baptiste. "Etude préclinique évaluant l'utilisation de la fraction vasculaire stromale et les cellules souches dérivées de tissu adipeux dans le traitement des myosites." Electronic Thesis or Diss., Normandie, 2023. http://www.theses.fr/2023NORMR054.
Abstract:
Les myosites représentent un ensemble de maladies musculaires auto-immunes touchant les muscles squelettiques et conduisant à des atteintes graves. Si la plupart des patients répondent aux traitements conventionnels, certains restent réfractaires. La fraction vasculaire stromale (FVS), fraichement extraite du tissu adipeux, ou les cellules souches en dérivant (ADSC) par culture d’amplification ont montré des résultats prometteurs dans différentes pathologies auto-immunes et pourraient permettre la prise en charge de ces patients. Afin d’évaluer leur potentiel et d’étudier les mécanismes d’action de ces thérapies, nous avons réalisé des études précliniques in vitro et in vivo. Pour cela, nous avons caractérisé et utilisé un modèle murin de myosites, la souris NOD Icos-/-, présentant des atteintes musculaires spontanées associées à des infiltrats leucocytaires importants. Afin de se rapprocher de l’utilisation autologue de ces thérapies, nous avons réalisé des greffes syngéniques de FVS et d’ADSC dans ce modèle. Nous avons pu observer un ralentissement de l’évolution de la symptomatologie, une réduction de la perte de force musculaire ainsi qu’une diminution de l’atrophie musculaire in vivo. Nous avons mis en évidence une meilleure efficacité des ADSC, en particulier lors des tests in vitro. Ces tests réalisés avec des cellules de donneurs, évaluant l’efficacité de la régénération (test de formation de colonies fibroblastiques) et l’effet immunomodulateur (test d’inhibition de la prolifération lymphocytaire), ont permis de démontrer l’effet dose-dépendant de ces thérapies ainsi que la supériorité des ADSC à la fois en termes d’efficacité maximale et de dose inhibitrice de 50% de l’effet immunomodulateur. Ils nous ont aussi permis d’identifier des marqueurs prédictifs des effets prolifératif (CD90, CD105 ou encore le taux élevé de cellules souches hématopoïétiques) et immunomodulateur (CD73 ou le taux de macrophages) de ces thérapies. L’ensemble de ces éléments démontrent le potentiel de ces thérapies dans le traitement des myosites et l’intérêt d’investiguer leur effet au travers d’essais cliniquesMyositis is a group of autoimmune muscular diseases affecting skeletal muscles, leading to severe damage. While most patients respond to conventional treatments, some remain refractory. The stromal vascular fraction (SVF), freshly extracted from adipose tissue, or stem cells derived from it (ADSC) by expansive culture have shown promising results in various autoimmune pathologies and could enable the management of these patients. To assess their potential and study the mechanisms of action of these therapies, we carried out preclinical studies in vitro and in vivo. To this end, we characterized and used a mouse model of myositis, the Icos-/- NOD mouse, showing spontaneous muscle damage associated with extensive leukocyte infiltrates. To be closer of the autologous use of these therapies, we performed syngeneic transplants of FVS and ADSC in this model. We observed a slowdown in the progression of symptoms, a reduction in the loss of muscle strength and a decrease in muscle atrophy in vivo. We have demonstrated a greater efficacy of ADSCs, particularly in in vitro assays. These tests, carried out with donor cells and assessing regenerative efficacy (fibroblast colony forming unit assay) and immunomodulatory effect (lymphocyte proliferation inhibition assay), demonstrated the dose-dependent effect of these therapies, as well as the superiority of ADSCs in terms of both maximum efficacy and 50% inhibitory dose of the immunomodulatory effect. They also enabled us to identify markers predictive of the proliferative (CD90, CD105 or high hematopoietic stem cell count) and immunomodulatory (CD73 or macrophage count) effects of these therapies. All these elements demonstrate the potential of these therapies in the treatment of myositis, and the interest of investigating their effect through clinical trials
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Castelló, Carla Martí. "Ultrassonografia do tumor sólido de Ehrlich inoculado em camundongos." Universidade Federal de Goiás, 2017. http://repositorio.bc.ufg.br/tede/handle/tede/7130.
Abstract:
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The research to prevent cancer, diagnose early, and find new therapies is one of the main challenges of current medicine, and in vivo tumor models are essential for this aim. Imaging techniques, such as ultrasound, assists the research by helping to obtain data that are more accurate and to reduce the number of animals necessary to obtain statistically significant results. Ehrlich carcinoma is one of the most widely used models but it has not an ultrasonographic description. In this study, serial ultrasound examinations were performed, in B-mode and Doppler, on Ehrlich solid carcinomas (ESC) inoculated in mice. From the measurements obtained by ultrasound, the growth patterns were analyzed and the tumors were separated in two groups depending on the specific growth rate (SGR). Ultrasonographic characteristics of capsule, margins, echotexture, vascular flow, and Doppler indices of Resistivity Index (RI) and Pulsability Index (PI) were compared between groups. ESC presents variable growth patterns; a capsule detectable by ultrasound, which sometimes present discontinuity; detectable flow in most of the exams; and the possibility of a central focus of necrosis or several necrosis focuses separated by tissue. In conclusion, tumors with high vascularization tend to have high SGR, while tumors that presented homogeneous echotexture and absence of blood flow tend to have lower SGR. The study also showed that changes in tumor vessels are reflected in Doppler indices, with significantly lower RI and PI, than normal vessels
A pesquisa para o diagnóstico precoce, prevenção e novos tratamentos do câncer é um dos principais desafios da medicina atual e os modelos tumorais in vivo são imprescindíveis para esse fim. Técnicas de imagem, como a ultrassonografia, auxiliam a obter dados mais precisos e diminuir o número de animais para obter resultados estatisticamente significativos. O carcinoma de Ehrlich é um dos modelos mais usados, mas não existem descrições ultrassonográficas dele. Nesse trabalho, foram realizados exames ultrassonográficos seriados, em modo-B e Doppler, em carcinomas sólidos de Ehrlich (ESC) inoculados em camundongos. A partir das medidas obtidas por ultrassom, foram analisados os padrões de crescimento e os tumores foram separados em dois grupos dependendo da taxa específica de crescimento (SGR). Foram comparadas as características ultrassonográficas da capsula, margens, ecotextura, distribuição e quantidade de fluxo e os índices Doppler, Índice de Resistividade (IR) e Índice de Pulsabilidade (IP), entre os grupos. Os ESCs apresentaram-se como tumores com padrões de crescimento variáveis; uma capsula detectável por ultrassonografia, mas que pode apresentar descontinuidade em alguns casos; fluxo detectável na maioria dos exames; e que podem apresentam um foco de necrose central ou vários focos de necrose separados. Conclui-se que os tumores que apresentam alta vascularização tendem a ter alta SGR enquanto os que apresentam ausência de fluxo e ecotextura homogênea estão correlacionados com baixa SGR. O estudo também demonstrou que as alterações e mudanças nos vasos tumorais se encontram refletidas nos índices Doppler, apresentando IR e IP significativamente menores as dos vasos extratumorais.
3
Zgheib, Sara. "Altérations physiologiques et récupération à long terme dans un modéle murin de séparation associée à une restriction du temps d'accés à l'alimentation : un outil pour l'étude des conséquences de l'anorexie mentale." Thesis, Littoral, 2014. http://www.theses.fr/2014DUNK0428/document.
Abstract:
L'anorexie mentale (AM) est un trouble du comportement alimentaire qui se caractérise par une recherche obsessionnelle de minceur, une forte réduction de la prise alimentaire et une distorsion de l'image de soi. Elle est associée à de multiples perturbations endocriniennes et métaboliques, et à une altération de la masse et de la microarchitecture osseuses. Les facteurs et les mécanismes qui interviennent dans cette maladie sont très mal connus ce qui limite les options thérapeutiques. Il est donc nécessaire de développer un modèle animal qui reproduise les perturbations physiologiques observées en AM et permette d'étudier les facteurs associés à l'altération osseuse. Dans ce but nous avons développé un modèle murin avec une restriction du temps d'accès à l'alimentation associée à un stress induit par la séparation (separation-based anorexia, SBA). Cette phase SBA de 10 semaines est suivie d'une phase de récupération en conditions standard (REC) de 10 semaines. Chez les souris femelles C57B1/6 en fin de croissance rapide, la phase SBA induit une perte rapide et importante du poids corporel. L'analyse de la composition corporelle par DEXA révèle une diminution rapide de près de 40% de la masse grasse ainsi qu'une baisse progressive de la masse maigre et un arrêt de l'acquisition de la masse osseuse. Au niveau des tibias, la densité minérale cortical et la microarchitecture trabéculaire sont altérées. L'observation des frottis vaginaux et la mesure des ovaires révèlent une perturbation importante des fonctions reproductrices. Les tests de tolérance au glucose ont montré que les souris SBA ont une capacité très élevée à corriger la glycémie. Ces animaux sont fortement hypoleptinémiques, et l'axe GH-IGF-1 est très perturbé. L'étude de l'expression génique de différents tissus adipeux a montré une augmentation du niveau des marqueurs de lipogénèse et de lipolyse, ainsi qu'une forte induction du phénotype "adipocyte brun" dans le tissu adipeux sous-cutané. Après deux semaines de REC, les souris SBA retrouvent très rapidement leur poids corporel, leurs masses maigre et grasse. La masse minérale toujours basse à ce stade est corrigée après 10 semaines de REC, ainsi que la microarchitecture osseuse (étude préliminaire). Tous les autres paramètres étudiés sont normalisés, sauf l'hypoleptinémie qui étonnamment persiste même après 10 semaines de protocol REC et malgré la normalisation de la masse adipeuse. D'après ces résultats, on peut conclure que le modèle SBA reproduit de nombreuses perturbations physiologiques observées en AM. La phase de REC révèle que ces souris ont une importante capacité de récupération. L'hypoleptinémie persistante pourrait favoriser la récupération. L'identification des mécanismes impliqués pourrait fournir des pistes thérapeutiques afin de favoriser la reconstitution du capital osseux des patientes anorexiquesAnorexia nervosa (AN) is an eating disorder mainly developed in adolescent girls and young women. It is characterized by an obsessive search for thinness, a profound undernutrition and a distorted self-image.It is associated with multiple endocrine and metabolic disturbances, decreased bone mass and microarchitectural alteration. Some of the developed adaptations are supposed to be involved in the blockade of the pathologic state. Unfortunately, these adaptations are poorly known and most of them cannot be studied on patients. So it is necessary to develop an animal model which mimics the main consequences observed in human pathology and allows studying the recovery process. For this purpose we adapted a murine model of time restricted feeding associated with chronic stress induced by separation-based anorexia (SBA). C57B1/6 female mice are submitted to a long term SBA protocol (10 weeks) and then a long term phase of recovery (10 weeks). At the beginning of the protocol mice are 8 weeks old, so their fast growth is finishing. SBA protocol induced a rapid and significant loss of body weight. Body composition analysis by DEXA showed a 40% decrease of the fat mass, a progressive loss of lean mass and a blockade of bone mass acquisition. Mice deveoped a high glucose tolerance. The observation of vaginal smears revealed a disruption of the estrous cycle and ovarian histology showed an atrophy of the ovaries. These two alterations suggest a major alteration of reproductive functions. These animals showed a very low leptinemia, and the GH/IGF-1 axis was disrupted. The study of bone alteration by microtomography indicated an alteration of bone microarchitecture and of cortical bone mass, mimicking osteoporosis often described in AN patients. Body weight, lean and fat masses were normalized quickly during the REC protocol. Bone mineral content still low after 2 weeks of REC protocol was fully corrected after 10 weeks. The estrous cycle ovarian size and the GH/IGF-I were normalized. Surprisingly, hypoleptinemia persisted even after 10 weeks of REC and despite the normalization of the fat mass. This result has been confirmed by the low level of leptin gene expression in various adipose tissues. Finally, the SBA protocol is valuable model of AN because numerous physiological alterations described in AN are mimicked in this model. The recovery phase revealed the high capacity of mice to normalize the long term alterations. Persitent hypoleptinemia could contribute to the normalization of body composition. However, the balance between central and peripheral effects of the uncorrected hypoleptinemia remains to be determined. This persisting hypoleptinemia could be used for the revision of the therapeutic strategies aiming to correct AN-induced osteoporosis
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Pereira, Beatriz Aparecida Soares. "Patogenicidade e imunogenicidade de isolados clínicos do complexo Paracoccidioides brasiliensis." Botucatu, 2019. http://hdl.handle.net/11449/181206.
Abstract:
Orientador: Rinaldo Poncio MendesResumo: Introdução. A correlação entre gravidade da paracoccidioidomicose e patogenicidade e imunogenicidade dos fungos causadores tem sido pouco investigada e foi o objetivo deste estudo. Metodologia. As cincos cepas Pb192, Pb234, Pb326, Pb417 e Pb531 foram identificadas pelo seqüenciamento da região Exon 2 da gp43. A patogenicidade foi determinada pelo cálculo da dose letal 50% (DL50%) e pela contagem do número de unidades formadoras de colônias, realizada na sexta semana pós-infecção de camundongos BALB/c. A imunogenicidade foi determinada pela avaliação da resposta imune humoral específica, utilizando-se a reação de imunodifusão dupla em gel de ágar e da imunidade celular, determinada pela concentração das citocinas interleucina -2, interleucina-10, interferon-γ, fator de necrose tumoral – α e do fator de crescimento do endotélio vascular, em tecido pulmonar. Quatro amostras clínicas foram recém-isoladas de pacientes com paracoccidioidomicose, provenientes da Região de Botucatu - os isolados Pb234 e Pb417, de pacientes com a forma crônica moderada; o Pb326 de um caso com a forma aguda grave; e o Pb531, de um caso com a forma crônica grave. As demais cepas Pb192, Pb01 e 8334 foram cedidas pelo laboratório de Moléstias infecciosas. Resultados. As cepas Pb417 e Pb326 agruparam-se às cepas identificadas como P. brasiliensis S1a, a Pb531 às P. brasiliensis S1b e as cepas Pb234 e Pb192 às cepas depositadas como P. restrepiensis (PS3). Os resultados demonstraram correlação direta entre ... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Introduction. The investigation of paracoccidioidomycosis and pathogenicity and immunogenicity of the provoking fungi has been little investigated and was the objective of this study. Methodology. As strains, Pb192, Pb234, Pb326, Pb417 and Pb531 were included by sequencing the Exon 2 region of gp43. The pathogenicity was determined by calculating the 50% lethal dose (LD50%) and by counting the number of colony forming units performed in the sixth week post-infection of BALB / c mice. Immunogenicity was determined by the humoral immune response, using the agar gel immunodiffusion reaction and the cellular immunity, determined the concentration of cytokines interleukin-2, interleukin-10, interferonγ, tumor necrosis factor - and factor of vascular endothelial growth in lung tissue. Surgical has been associated with patients with paracoccidioidomycosis, derived from the Botucatu - the Pb234 and Pb417; the Pb326 of a case with a severe severe form; and Pb531, of a case with severe chronic form. The other strains Pb192, Pb01 and 8334 were transferred by the laboratory of Infectious Diseases. Results. Pb417 and Pb326 strains were grouped into the associated strains P. brasiliensis S1a, Pb531 to P. brasiliensis S1b and strains Pb234 and Pb192 to strains deposited as P. restrepiensis (PS3). The results demonstrate the pathogenicity of disease error and severity. The small LD 50 values were measured in the following cases: severe disease, Pb531 and Pb326. Pb531 strain was considered to... (Complete abstract click electronic access below)
Mestre
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Silva, Muriel Vilela Teodoro. "Avaliação do efeito da expressão do gene da interleucina 32 (IL-32) humana em modelo murino de infecção por Leishmania (Leishmania) amazonensis." Universidade Federal de Goiás, 2016. http://repositorio.bc.ufg.br/tede/handle/tede/6333.
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Fundação de Amparo à Pesquisa do Estado de Goiás - FAPEG
IL-32 is a proinflammatory cytokine which has different isoforms. IL-32γ isoform is the most powerful and was detected in lesions of patients with cutaneous leishmaniasis. Murine cells respond to IL-32, however mice lack the gene for this cytokine. To understand the role of IL- 32 in Leishmania (L.) amazonensis, we used transgenic mice for human IL-32γ (IL-32γTg). C57BL/6 mice (WT) and C57BL/6 IL-32γTg were infected with L. amazonensis promastigotes in the ear. The lesion development was followed weekly with a digital caliper (measured in mm of injury). After 3, 6 and 9 weeks, the animals were euthanized for tissue parasitism analysis by the limiting dilution technique, in infected ears, draining lymph node and spleen of mice. The draining lymph node cells were incubated (48 h) in the presence or absence of L. amazonensis antigen (Ag) for analysis of cytokines by ELISA. IL-32γTg mice present IL-32 production in spleen, liver, lymph node and ear. IL-32γTg mice have a lower injury than the WT mice during the third week of infection. From the 5th to the 9th week of infection, the two groups had similar lesion development profiles. Interestingly, in the 3rd week of infection, the parasitic load in the lesion of IL-32γTg mice was 100 times greater than that of WT mice. After three weeks, IL-32γTg mice maintained the same parasitic load up to nine weeks. In WT mice, however, the number of parasites increased exponentially during weeks evaluated. The parasite load in the spleen and lymph node was lower in IL-32γTg mice when compared with WT mice. There was no difference in histological sections of the lesions in WT and IL-32γTg mice infected with L. amazonensis. We did not observe differences between WT and IL-32γTg groups on the product -10) by lymph node cells stimulated with Ag, in the 3rd, 6th and 9th week of infection. Our data suggest that IL-32γ favors infection by L. amazonensis in the early stages, allowing the growth of the parasites. However, this cytokine seems to limit the growth and spread of parasites in the later stages of infection. In vitro analyzes show the similar percentage of infected cells and the number of parasites per infected cell in WT macrophages and IL-32γTg after 3 and 48h of infection with L. amazonensis. However, the production of NO by macrophages seems to be lower in IL- 32γTg mouse cells during infection with L. amazonensis. Understanding the mechanisms by which IL-32γ modulates Leishmania amazonensis infection in mice is essential to define the components that control cutaneous leishmaniasis caused by this specie in humans.
A IL-32 é uma citocina pró-inflamatória que apresenta diferentes isoformas. A isoforma IL- 32γ é a mais potente e foi detectada em lesões de pacientes com leishmaniose tegumentar americana. Células murinas respondem à IL-32, no entanto, camundongos não têm o gene para essa citocina. Para entender o papel da IL-32 na infecção por Leishmania (Leishmania) amazonensis, foram utilizados camundongos transgênicos para a IL-32γ humana (IL-32γTg). Camundongos C57BL/6 (WT) e C57BL/6 IL-32γTg foram infectados com formas promastigotas de L. amazonensis na orelha. O desenvolvimento da lesão foi acompanhado semanalmente com paquímetro digital (medida em mm de lesão). Após 3, 6 e 9 semanas, os animais foram eutanasiados para análise de parasitismo tecidual, pela técnica de diluição limitante, nas orelhas infectadas, no linfonodo drenante e no baço dos camundongos. As células do linfonodo drenante foram incubadas (48 h), na presença ou ausência de antígeno de L. amazonensis (Ag), para análise de citocinas pela técnica de ELISA. Camundongos IL- 32γTg apresentam produção de IL-32 no baço, fígado, linfonodo e orelha. Camundongos IL- 32γTg apresentam uma lesão menor do que a lesão dos camundongos WT, na terceira semana de infecção. Da 5ª até a 9a semana de infecção, os dois grupos apresentaram perfis semelhantes de desenvolvimento da lesão. Curiosamente, na 3ª semana de infecção, a carga parasitária na lesão do camundongo IL-32γTg era 100 vezes maior do que a dos camundongos WT. Após três semanas, os camundongos IL-32γTg mantiveram a mesma carga parasitária até nove semanas. Em camundongos WT, no entanto, o número de parasitos aumentou exponencialmente durante as semanas avaliadas. A carga parasitária do linfonodo e no baço foi menor nos camundongos IL-32γTg, quando comparado com camundongos WT. Não foi observada diferença nos perfis histológicos das lesões nos camundongos WT e IL-32γTg infectados por L. amazonensis. Não foi observada nenhuma diferença entre os grupos WT e IL-32γTg em relação à produção de citocinas (IFNγ, TNFα e IL-10), pelas células dos linfonodos estimuladas com Ag, na 3a, 6a e 9a semana de infecção. Os nossos dados sugerem que a IL-32γ favorece a infecção por L. amazonensis nas fases iniciais, permitindo o crescimento do parasito; no entanto, essa citocina parece limitar o crescimento e a disseminação dos parasitos nas fases mais tardias da infecção. As análises in vitro mostraram porcentagem de células infectadas e número de parasitas por célula infectada semelhantes nos macrófagos dos WT e IL-32γTg com 3 e 48h de infecção por L. amazonensis. Entretanto, a produção de NO por macrófagos parece ser menor nas células de camundongos IL-32γTg durante a infecção por L. amazonensis. Compreender os mecanismos pelos quais a IL-32γ modula a infecção por L. amazonensis nos camundongos é fundamental para a definição dos componentes que controlam a leishmaniose tegumentar causada por esta espécie em seres humanos.
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Zapana, Priscila Rosse Mamani. "Desenvolvimento de um modelo murino para estudo da resposta imune conferida pela proteína do Nucleocapsídeo do vírus Oropouche." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/17/17147/tde-25042018-153023/.
Abstract:
O vírus Oropouche (OROV) é um arbovírus que ocorre na região amazônica causando surtos de doenças febris agudas e que, ocasionalmente, podem ser associados a meningoencefalite. Aproximadamente 500.000 casos de Oropouche teriam ocorrido no Brasil. Entretanto, não existe vacina contra o OROV. O objetivo deste trabalho foi desenvolver um modelo animal de infecção por OROV para estudar a patogênese da doença e um modelo para testar candidatas vacinais. Protótipo vacinal utilizando a proteína recombinante do nucleocapsídeo (N) de OROV (NrOROV), que é o principal antígeno viral, foi usado como potencial candidato para vacina. Neste estudo utilizou-se um modelo animal em camundongos Balb/c de 12 semanas de idade, inoculados intracerebralmente com 8x105 PFU de OROV, capaz de induzir 100% de letalidade após o terceiro dia da infecção. Altos títulos virais foram encontrados no cérebro e na medula espinhal dos animais. Surpreendentemente, 12 e 24 horas pós-infecção foi possível detectar vírus no fígado e baço (3 Log10 PFU/g) dos camundongos. Com este modelo foram testados os candidatos vacinais. Grupos de camundongos foram imunizados 3 vezes com OROV, OROV e FCA, NrOROV, NrOROV e FCA, NrOROV, Poli I:C e Montanide ISA 720. Após 3 imunizações, os animais foram desafiados com 10 LD50 de OROV e observados por 20 dias. Os animais imunizados com NrOROV e adjuvantes, não foram capazes de produzir anticorpos neutralizantes e adquirir imunidade protetora contra OROV enquanto que os imunizados com OROV apresentaram altos níveis de anticorpos neutralizantes e completa proteção in vivo. Ainda, os anticorpos produzidos pelos animais imunizados permitiram estudar o ciclo de replicação celular do OROV utilizando imunofluorescência.Oropouche (OROV) is an arbovirus that occurs in the South American, Amazon region, producing outbreaks of acute febrile illness occasionally associated to meningoencephalitis. Approximately 500,000 cases of Oropouche have been reported in Brazil in the last 60 years. However, there is no available vaccine for OROV. We show here the development of an animal model of OROV suitable for studies on pathogenesis and vaccine testing. A vaccine prototype based on recombinant OROV nucleocapsid protein (NrOROV), an important viral antigen, was evaluated in the animal model. Initialy, we observed that all 12-week-old Balb/c mice inoculated intracerebrally with 8x105 PFU died after the third day of infection. Surprisingly, OROV genome was detectable in the liver as early as 12 hours post infection (pi) and in the spleen at 24 hours pi at 3 log10 PFU/g. Besides, high viral titers were found in brain and spinal cord. To test the NrOROV as a vaccine candidate, animals divided in 5 groups were immunized subcutaneously 3 times, two weeks apart with either OROV, OROV and Freud complete Adjuvant (FCA), NrOROV, NrOROV and FCA, NrOROV and Poly I:C and Montanide ISA 720. The experiment also included a group of naïve animals. After the third immunization, the animals were challenged with 10LD50 by intracerebral route and followed for 20 days. The animals immunized with NrOROV and adjuvants developed specific antibodies that were not able to neutralize the virus or confer protective immunity against OROV. Nevertheless, mice immunized with OROV showed high levels of neutralizing and protective antibodies. Despite the discouraging results with NrOROV as a vaccine, the mouse model is suitable to study pathogenesis, and to test other vaccines for OROV.
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DE, PONTI GIADA. "Exploring early therapeutic approaches in a Mucopolysaccharidosis type I (MPS I) mouse model." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2022. http://hdl.handle.net/10281/382061.
Abstract:
In questo progetto di dottorato, sono stati presi in considerazione alcuni punti cruciali relativi alla malattia Mucopolisaccaridosi di tipo I (MPSI) e ai limiti delle attuali terapie, per migliorarle concentrandosi su approcci in epoca neonatale, a livello di combinazione terapeutiche (HSCT e ERT) e di terapia genica, e su riduzione delle tossicità associate ai regimi di condizionamento. Complessivamente, le problematiche più significative riguardo MPSI rimangono la necessità di un intervento precoce e rapido, l’incompleta correzione della malattia in seguito agli attuali approcci terapeutici e gli effetti collaterali dovuti al regime di precondizionamento. La prima parte del progetto si è concentrata sul testare un approccio terapeutico che combinasse i trattamenti canonici per MPSI. È stata testata l'efficacia della combinazione di HSCT ed ERT nel modello murino di MPSI come intervento neonatale, per valutare i benefici aggiuntivi della terapia enzimatica effettuata in modo continuativo a seguito del trapianto di cellule da donatore. Tre opzioni di trattamento sono state confrontate dalla nascita, considerando la mancante attività enzimatica (IDUA), l’accumulo di GAG e di vacuoli nei principali organi viscerali, la risposta nei confronti di IDUA ricombinante e i miglioramenti di tipo scheletrico e cerebrale. Pertanto, un approccio combinato di HSCT ed ERT nel periodo neonatale potrebbe essere applicato per migliorare alcune manifestazioni cliniche di MPSI, soprattutto evitando danni irreversibili. La seconda parte del progetto di dottorato è stata svolta in collaborazione con TIGET-SR e il Prof. Alessandro Aiuti. Si è concentrato sulla sperimentazione di un approccio di terapia genica neonatale in un modello murino di MPSI, considerando l'importanza di correggere precocemente la malattia. In particolare, abbiamo valutato se questo trattamento terapeutico potesse essere applicato nei neonati MPSI e potesse essere una strategia efficace per superare i principali problemi clinici che permangono dopo il trattamento canonico. Abbiamo valutato l'effetto della terapia genica somministrata nei neonati affetti da MPSI, monitorando i valori di IDUA e VCN nel sangue periferico e considerando infine la mancante attività enzimatica (IDUA), l’accumulo di GAG e di vacuoli nei principali organi viscerali, la risposta nei confronti di IDUA ricombinante e i miglioramenti di tipo scheletrico e cerebrale. Contemporaneamente, abbiamo cercato di ridurre gli effetti collaterali causati dal regime di condizionamento nel contesto delle terapie neonatali per MPSI, come progetto parallelo. L’obiettivo principale è stato trasporre l'applicazione di ADC, molecole congiunte di anticorpo-farmaco, capaci di agire specificatamente sulla cellula, come condizionamento per il trattamento neonatale di MPSI, in cui un intervento precoce è fondamentale. Poiché nessuna delle opzioni testate è stata in grado di indurre un sufficiente attecchimento di cellule del donatore da essere rilevante per il trattamento precoce dell'MPSI, ne abbiamo ricercato le cause, dimostrando la necessità di ulteriori studi prima dell'applicazione degli ADC nel modello studiato, in quelli umanizzati e nei cuccioli di MPSI NSG. Analisi preliminari sono state effettuate relativamente all’aumento dei livelli di citochine dopo CD117-SAP nei topi NSG adulti, confrontandoli agli altri regimi di condizionamento, per valutare una possibile applicazione di ADC con farmaci antinfiammatori prima della terapia precoce nei cuccioli MPSI.The present PhD project has taken into account critical issues around Mucopolysaccharidosis type I (MPSI) and limitations of current therapies to further improve them, by generally focusing on neonatal therapeutic approaches, both in terms of combined HSCT and ERT and of gene therapy, and on trying to reduce the overall toxicities associated with pre-conditioning settings. Overall, the most important open issues regarding this rare life-threatening disorder are the need for a precocious and rapid intervention, the lack of complete disease correction after current therapeutic approaches and side effects due to pre-conditioning regiment. My PhD project partially focused on testing a combined approach of the current standard-of-cares for treating MPSI. HSCT and ERT combination efficacy was tested in a mouse model of MPSI as neonatal intervention, for evaluating additional benefits of continuous enzyme therapy after transplant of donor’s cells. We compared three treatment options starting from MPSI pups’ birth, considering IDUA deficient activity, GAGs storage and vacuoles in visceral organs, the immune response against the recombinant IDUA and skeletal and CNS ameliorations. Therefore, performing a combined approach of HSCT and ERT in the neonatal period could help improving some hard-to-treat MPSI manifestations. The second part of this PhD project was carried out in collaboration with TIGET-SR and Prof. Alessandro Aiuti. It was focused on testing a neonatal gene therapy approach in a mouse model of MPSI, considering the importance of an early phenotype correction. In particular, we evaluated if this early treatment could be applied in MPSI neonates and could be a successful strategy for overcoming the main clinical issues that still remain after current canonical HSCT treatment. We monitored peripheral blood of treated mice for 8 months in terms of enzymatic activity and VCN, and we evaluated the effect of GT performed in MPSI pups at endpoint, considering IDUA deficient activity, vector copies/genome, GAGs storage and vacuoles in visceral organs, the immune response against the recombinant IDUA and skeletal and CNS ameliorations. The last part of this PhD project was centered on trying to reduce the high morbidity and mortality due to the severe conditioning regimen in the context of neonatal MPSI therapies, as a side project. The main objective was to translate the application of hematopoietic cell–specific antibody-drug conjugates (ADCs) as conditioning for early MPSI treatment, in which a precocious intervention is crucial. Since none of the tested setting was able to induce enough engraftment of donor’s cells to be relevant for MPSI early treatment, we tried to understand what could interfere, but we demonstrated the need for further studies prior to ADCs application in humanised models and in MPSI NSG pups. Preliminary results on increased cytokines levels after CD117-SAP in adult NSG compared to other conditioning settings were performed to evaluate impairment of inflammation and possible ADC application with anti-inflammatory drugs prior to early therapy in MPSI pups.
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Palma, Luana Carneiro. "Doença esteatóica não alcoólica do fígado: comparação das alterações histológicas hepáticas entre modelo murino e pacientes obesos." Centro de Pesquisas Gonçalo Moniz, 2013. https://www.arca.fiocruz.br/handle/icict/7149.
Abstract:
Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2013-10-15T15:33:27Z
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Universidade Federal da Bahia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil
A Doença Esteatótica Não Alcoólica do Fígado (do inglês Nonalcoholic Fatty Liver Disease – NAFLD) é uma doença crônica hepática de caráter espectral, que vai desde a esteatose simples até a esteato-hepatite não alcoólica. A progressão para cirrose e carcinoma hepatocelular têm sido descrita. A NAFLD apresenta aspectos histológicos semelhantes à doença hepática relacionada ao álcool (esteatose, inflamação lobular, corpúsculos de Mallory e fibrose), mas acomete indivíduos com história negativa de consumo excessivo de álcool. A NAFLD é uma das principais doenças crônicas hepáticas mundiais, e os indivíduos obesos representam a maioria dos casos da doença. Os mecanismos envolvidos na progressão da esteatose para esteato-hepatite não são bem compreendidos. Neste aspecto, modelos murinos da NAFLD têm sido frequentemente utilizados para elucidação destes mecanismos. A maioria dos modelos disponíveis é resultante de modificações genéticas e/ou nutricionais e, em geral, não simulam as alterações metabólicas e histológicas comumente vistas em pacientes com NAFLD. Em nosso grupo, foi proposto um novo modelo de NAFLD. Camundongos C57BL/6 alimentados com dieta rica em gordura (High Fat - HF) demonstraram alterações metabólicas e histológicas sugestivas de NAFLD. O objetivo do presente trabalho foi comparar alterações histológicas hepáticas presentes nestes camundongos com as alterações observadas em pacientes obesos. Amostras de fígados de pacientes obesos e de camundongos alimentados com a dieta HF foram utilizadas. Os tecidos hepáticos foram corados em Hematoxilina & Eosina e Picrossírius Red para avaliação das alterações hepáticas (esteatose, balonização, inflamação, corpúsculos de Mallory-Denk e fibrose). Além disso, foi realizada imunoistoquímica para avaliação da presença de células estrelares ativadas e de células progenitoras hepáticas, células envolvidas na fibrose e no desenvolvimento de carcinoma hepatocelular, respectivamente. Os resultados demonstraram que os fígados de todos os pacientes obesos exibiram esteatose macrovacuolar, balonização hepatocelular, inflamação lobular e fibrose perissinusoidal, o que caracterizou estes pacientes como portadores da NAFLD. As mesmas alterações foram observadas em fígados de camundongos alimentados com a dieta HF. As células estrelares ativadas foram observadas em todos os pacientes obesos, assim como em camundongos de dieta HF. As células progenitoras hepáticas foram observadas na maioria dos pacientes obesos. O fígado de todos os camundongos alimentados com dieta HF exibiram células progenitoras hepáticas. A partir dos dados obtidos, pode-se concluir que fígados de camundongos alimentados com dieta HF exibem alterações histológicas hepáticas similares às observadas em pacientes obesos. Isto abre perspectivas para a utilização do modelo proposto em estudos que busquem elucidar os mecanismos envolvidos na patogênese da NAFLD.
Nonalcoholic Fatty Liver Disease (NAFLD) is a chronic liver disease ranging from simple steatosis to nonalcoholic steatohepatitis. The progression to cirrhosis and hepatocellular carcinoma has been reported. The NAFLD shows histological features similar to alcohol-related liver disease (steatosis, lobular inflammation, fibrosis and Mallory-Denk bodies), but affects individuals with no history of excessive alcohol consumption. The NAFLD is a major chronic hepatic disease in the world, and obese individuals represent the majority of cases of the disease. The mechanisms involved in the progression of steatosis to steatohepatitis are not well understood. In this regard, murine models of NAFLD have been frequently used for elucidation of these mechanisms. Most available models are the result of genetic or nutritional modifications, and generally do not mimic metabolic and histologic changes commonly seen in patients with NAFLD. In our group, we have proposed a new model of NAFLD. Mice fed high fat diet (HF diet) demonstrated metabolic and histological features suggestive of NAFLD. The aim of this study was to compare liver histological alterations present in these mice with the changes observed in obese patients. Samples of livers of obese patients and mice fed HF diet were used. For assessment of liver alterations, such as steatosis, ballooning, inflammation, Mallory- Denk bodies and fibrosis, tissues were stained with hematoxylin & eosin and picrossirius red. In addition, the presence of activated stellate and progenitor liver cells was estimated using immunohistochemistry. The results show that the livers of all obese patients exhibited macrovesicular steatosis, hepatocellular ballooning, perisinusoidal fibrosis, and lobular inflammation, which characterized these patients with NAFLD. Similar changes were observed in livers of mice that fed the HF diet. Activated stellate cells were observed in all obese patients as well as in mice HF. Hepatic progenitor cells were observed in most obese patients. The liver of all animals fed the HF diet exhibited liver progenitor cells. From the data obtained, it can be concluded that livers of mice fed with HF diet exhibit liver abnormalities similar to those observed in obese patients. This opens perspectives for the use of the proposed model in studies that seek to elucidate the mechanisms involved in the pathogenesis of NAFLD.
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Fercoq, Frédéric. "Interactions filaire/poumon dans le modèle murin de filariose Litosomoides sigmodontis." Thesis, Paris, Muséum national d'histoire naturelle, 2017. http://www.theses.fr/2017MNHN0018/document.
Abstract:
Les filaires sont des nématodes parasites transmis à des vertébrés par des arthropodes hématophages. Les espèces filariennes qui s'installent dans les cavités cœlomiques, les vaisseaux lymphatiques ou des tissus conjonctifs ont leurs stades infestants (ou L3) qui migrent via le système lymphatique après leur inoculation dans la peau. En utilisant le modèle murin avec la filaire Litomosoides sigmodontis dont les adultes résident dans la cavité pleurale, deux phases d'interaction des filaires avec les poumons des souris BALB/c sont décrites 1) lors de la migration des L3 de la peau à la cavité pleurale ; 2) pendant la phase patente de l’infection quand les adultes pondent des microfilaires dans la cavité pleurale. Dans la 1ère phase les L3 rejoignent le système sanguin pulmonaire puis traversent les poumons pour entrer dans la cavité pleurale. Ce passage induit une pathologie aigue transitoire: tout d'abord des hémorragies consécutives à la rupture des capillaires pulmonaires, accompagnées d'une augmentation du nombre de neutrophiles pulmonaires et de la libération transitoire d'IL-1β et des alarmines IL-33 et S100A9 dans la cavité pleurale. Le S100A9 semble faciliter la survie des filaires, soit par un effet anti-inflammatoire soit en facilitant la migration des L3. Les neutrophiles peuvent libérer des NETS en réponse aux L3. Dans les jours suivant l'infection, une réponse régulatrice se met en place dans les poumons, avec le recrutement de macrophages et d'éosinophiles, la production d'IL-4, de CCL2 et d'IL9, ainsi que la baisse d'expression de molécules inflammatoires. La formation des granulomes est également observée dans le tissu pulmonaire. Le passage des L3 induit aussi une inflammation des vaisseaux sanguins pulmonaires chez les souris C57BL/6 seulement. Lors de la phase patente de l'infection, 40% des souris ne développent pas de microfilarémie sanguine. La comparaison des réponses des souris microfilarienne et amicrofilarienne montre une exacerbation de l'inflammation pleurale induite par les microfilaires. De plus, les souris microfilarémiques développent une pathologie pulmonaire dépendant des microfilaires consistant en la fibrose de la plèvre viscérale, une accumulation périvasculaire de macrophages et une inflammation bronchoalvéolaire (production de mucus et éosinophilie). Le contrôle des filaires (adultes et microfilaires), mais aussi la mise en place de la pathologie sont dépendantes de l'IL-5 et de l'IL-4RFilariae are parasitic nematodes transmited to vertebrates by haematophagous arthropods. The filarial species that settle in the coelomic cavities, the lymphatic vessels or the connective tissues have their infectious stages (or L3) which migrate via the lymphatic system after their inoculation into the skin. Using the murine model with the filaria Litomosoides sigmodontis, whose adults reside in the pleural cavity, two phases of interaction between filariae and the lung of BALB/c mice are described 1) during the L3 migration from the skin to the pleural cavity ; 2) during the patent phase of infection, when adults realease microfilariae in the pleural cavity. During the 1st phase L3 join the pulmonary blood system and then cross through the lungs to enter the pleural cavity. This passage induces a transient acute pathology: first haemorrhages following the rupture of the pulmonary capillaries, together with an increase in the number of pulmonary neutrophils and the transient release of IL-1β and the alarmins IL-33 and S100A9 in the pleural cavity. S100A9 appears to facilitate the survival of the filariae either by an anti-inflammatory effect or by facilitating the migration of L3. Neutrophils can release NETs in response to L3. Within days following the infection, a regulatory response takes place in the lungs, with recruitment of macrophages and eosinophils, production of IL-4, CCL2 and IL-9, and downregulation of inflammatory molecules. The formation of granulomas is also observed in pulmonary tissue. The passage of L3 also induces an inflammation of pulmonary blood vessels, in C57BL/6 mice only. During the patent phase of the infection, 40% of the mice do not develop blood microfilaraemia. Comparison of responses of microfilaremic and amicrofilaremic mice shows an exacerbation of pleural inflammation induced by microfilariae. In addition, microfilaremic mice develop microfilaria-dependent pulmonary pathology consisting on fibrosis of the visceral pleura, perivascular accumulation of macrophages and bronchoalveolar inflammation (mucus production and eosinophilia). The control of the filariae (adults and microfilariae), but also the establishment of the pathology are dependent on IL-5 and IL-4R
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Babaie, Yasmin. "A murine model for haemangioblast transplantation." Thesis, University of Edinburgh, 2004. http://hdl.handle.net/1842/23691.
Abstract:
A promoter trap strategy was used to target a single allele of the flk-1 gene with one of two reporter constructs. One placed the EGFP reporter under flk-1 transcriptional control, while the other transcribed the selectable HPRT enzyme, which could be used to isolate flk-1 expressing cells in the HM1 hprt deficient ES cell line. Homologous recombination was successfully achieved with both targeting vectors. HPRT targeted selectable lines were successfully isolated. All lines showed appropriate transgene expression at high enough levels for effective HAT selection to isolate pure populations of flk-1 expressing cells. Two methods of deriving haemangioblastic progenitors from ES cells were tested for their efficacy of the isolation of a pure haemangioblast population based on the expression of flk-1. Methylcellulose cultures were found to be highly variable and problematic to carry out successfully whereas monolayer differentiation on collagen IV was more consistent. This system was then used to optimise the differentiation and selection regime applied to the flk-1/HPRT targeted cells in an attempt to isolate a pure haemangioblast progenitor population. Flk-1/HPRT targeted cells were marked with a constitutive GFP transgene, differentiated and selected for flk-1/HPRT expression on collagen IV. The selected cells were injected into the blastocyst stage embryo to see whether a developmentally more advanced cell population would survive and contribute to the expected cell lineages. Contribution of the GFP marked cells was observed in mesodermal and highly vascularised organs such as the heart, liver and kidney but was absent from the ectodermally derived brain. Expression was strongly localised around regions of vacularisation.
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Watkins, Alan D. "A murine model of pulmonary inflammation." Thesis, University of Southampton, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.395963.
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Bahdoudi, Seyma. "Etude des mécanismes cellulaires et moléculaires impliqués dans les effets neuroprotecteurs du gliopeptide OctaDecaNeuropeptide (ODN) dans un model murin de la Maladie de Parkinson." Thesis, Normandie, 2017. http://www.theses.fr/2017NORMR138/document.
Abstract:
La maladie de Parkinson (MP) est un trouble neurodégénératif caractérisé par une perte progressive de neurones dopaminergiques (DA) de la substance noire pars compacta (SNpc). Différents mécanismes sont associés à la neuropathogénèse de la MP et en particulier le dysfonctionnement de la chaîne respiratoire mitochondriale, le stress oxydatif, l’apoptose et les processus neuro-inflammatoires. L'octadécaneuropeptide (ODN) est un peptide dérivé du diazepam-binding inhibitor (DBI) exprimé par les cellules astrogliales, qui exerce une action neuroprotectrice dans un modèle cellulaire in vitro de la MP. A ce jour, aucune étude in vivo n’a été réalisée, afin de déterminer si les données obtenues sur les modèles cellulaires in vitro peuvent être transposées in vivo. Le projet de cette thèse consiste ainsi à mettre en évidence l’action protectrice de l’ODN sur la survie des neurones DA de la SNpc dans un modèle murin de la MP et à rechercher les conséquences de l’invalidation du gène du précurseur de l’ODN (DBI) sur la vulnérabilité des neurones DA. Les résultats obtenus montrent qu’une seule injection intra-cérébroventriculaire d’une faible quantité d’ODN (10 ng), 1 h après la dernière administration systémique de 1-méthyl-4-phényl-1,2,3,6-tétrahydropyridine (MPTP) prévient significativement la perte des neurones DA dans la substance noire et la dégénérescence de leurs prolongements nerveux vers le striatum comme mesuré par des marquages et des mesures d’expression de la tyrosine hydroxylase. Cet effet neuroprotecteur de l’ODN est accompagné par une réduction du nombre d’astrocytes réactifs, une forte inhibition de l'expression de gènes pro-inflammatoires tels que les interleukines (IL) IL-1β et IL-6, et tumor necrosis factor-α. De plus, l'ODN bloque l'inhibition du gène anti-apoptotique Bcl-2 et la stimulation des gènes pro-apoptotiques Bax et caspase-3, induite par le MPTP dans la SNpc et le striatum. L'ODN réduit également l’accumulation d'espèces réactives de l'oxygène (ROS) et de produits d'oxydation lipidique dans les neurones DA. Par ailleurs, les souris knock-out DBI (DBI-/-) sont plus vulnérables que les animaux sauvages (DBI+/+) vis-à-vis de la neurotoxicité du MPTP. L’absence de production d’ODN endogène, chez les souris DBI-/- parkinsoniennes, augmente les dommages cellulaires induits par le MPTP, la réactivité gliale, les taux de ROS, l’expression de cytokines pro-inflammatoires et l'activité de la caspase-3 dans la région nigro-striée. L’ensemble de ces résultats montre que le gliopeptide ODN exerce un puissant effet neuroprotecteur contre la dégénérescence des neurones DA de la SNpc induite par le MPTP, chez la souris. Cette action protectrice met en jeu des mécanismes impliquant l’inhibition des processus neuro-inflammatoires, oxydatifs et apoptotiques. D’autre part, la déficience en ODN potentialise les effets délétères du MPTP, suggérant que ce peptide joue un rôle clé lors de la réponse à un stress cellulaireParkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of loss of dopaminergic (DA) neurons within the substantia nigra pars compacta (SNpc). Different mechanisms are associated with the neuropathogenesis of PD including dysfunction of the mitochondrial respiratory chain, oxidative stress, apoptosis and neuroinflammatory processes. Octadecaneuropeptide (ODN) is a diazepam-binding inhibitor (DBI)-derived peptide, expressed by astrocytes, which protects neurons against oxidative cell damages and apoptosis in an in vitro model of PD. Nevertheless, its protective action in vivo has never been investigated. Therefore, the aim of the project of this thesis was to investigate whether intracerebroventricular (i.c.v) injection of ODN could prevent DA neuron degeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD, and to explore the vulnerability of ODN precursor knockout (DBI KO) mice to MPTP-induced neurotoxicity. The results show that a single i.c.v injection of 10 ng/μl ODN, 1 h after the last systemic administration of MPTP, prevents the reduction of the number of tyrosine hydroxylase (TH)-positive cell bodies and fibers in the SNpc and striatum, respectively. Immunofluorescence imaging, Western blot analysis and Q-PCR studies revealed that ODN totally abolished MPTP-induced decrease of TH positive cells, mRNA expression and protein levels. This neuroprotective effect of ODN is accompanied by a reduction in the number of reactive astrocytes, an inhibition of the expression of pro-inflammatory genes such as interleukins (IL) IL-1β and IL-6, and a decrease of tumor necrosis factor -α. In addition, ODN blocks the inhibition of the anti-apoptotic Bcl-2 gene and the stimulation of Bax and caspase-3 expression induced by MPTP in the SNpc and striatum. ODN also reduces the accumulation of reactive oxygen species (ROS) and lipid oxidation products in DA neurons. Furthermore, DBI-/- mice exhibited more vulnerability to MPTP than wild-type animals (DBI+/+). Thus, ODN KO mice are more sensitive to MPTP-induced inflammatory and oxidative brain damages, suggesting that the endogenous OD may also be neuroprotective. These results indicate that, based on its anti-oxidative, anti-inflammatory and anti-apoptotic effect, the gliopeptide ODN could lead to the development of effective therapeutic agents for the treatment of cerebral injuries involving oxidative neurodegeneration
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Nicolas, Sarah. "Mise en évidence du potentiel thérapeutique de l’adiponectine et de son rôle dans les effets antidépresseurs de l’environnement enrichi." Thesis, Université Côte d'Azur (ComUE), 2018. http://www.theses.fr/2018AZUR4019/document.
Abstract:
La dépression est une pathologie multifactorielle induisant des troubles psychiques et physiques. De nouvelles thérapies visant à enrichir l’environnement des patients par des activités physiques, sociales et cognitives aident à la rémission en complément des traitements pharmacologiques. Cependant les bases moléculaires sous-jacentes aux bénéfices observés dans ces thérapies sont méconnues. C’est dans ce contexte que nous avons étudié les effets de ces thérapies via la mise en place d’un modèle murin d’environnement enrichi (EE). L’objectif de ma thèse a été d’évaluer les effets antidépresseurs de l’EE sur un modèle murin de dépression et d’identifier une nouvelle cible thérapeutique. J’ai montré que l’administration chronique de corticostérone induit un état dépressif et une neuroinflammation qui peuvent être réversés par l’EE. De plus, mes travaux ont mis en évidence, l'adiponectine (ApN), comme étant un acteur clef des effets de l'EE. J’ai montré que l’EE via l’ApN était capable de limiter la neuroinflammation. Par ailleurs, la caractérisation de souris n’exprimant pas l’ApN a montré que ces souris étaient insensibles en partie aux effets de l’EE. Par la suite, je me suis intéressée à la voie de signalisation de l’ApN impliquée dans ses effets anti-inflammatoires, j’ai montré que l’ApN inhibe l’activation de la microglie en se liant à son récepteur AdipoR1. Enfin, j’ai testé l’effet de l’AdipoRon, un agoniste des récepteurs de l’adiponectine, sur des souris traitées par la corticostérone. J’ai montré que l’AdipoRon réduisait l’état « dépressif » de ces souris. Mon travaille suggère que les effets antidépresseurs de l’AdipoRon sont dus à sa pléiotropie car il agit simultanément sur différents systèmes altérés dans la dépression dont la neurogenèse hippocampique, la neurotransmission sérotoninergique et la neuroinflammation. Pour conclure ce travail met en avant les effets bénéfiques de l’EE sur la dépression et la neuroinflammation. De plus, ils identifient l’ApN et sa voie de signalisation comme de nouvelles cibles prometteuses dans le traitement de la dépressionMajor depression is a complex disorder characterized by behavioral and cognitive impairments triggered by various factors including genetic predispositions, stress and environment. The pathophysiology of depression is poorly understood. Numerous evidence suggests that neuroinflammation is associated with depression. Alternative therapeutic strategies are needed and "positive" life experiences could be an efficient way to help the remission of the disorder. To study the potential antidepressant effects of such “positive” living conditions, we used the enriched environment (EE) paradigm on mice. The aim of our work was to fully characterize the antidepressant and anti-inflammatory effects of EE in a well-characterized murine model of depression-like behavior induced by long-term administration of corticosterone. We showed that EE efficiently reverses the anxiety/depression‐like state of mice and reduces neuroinflammation. Moreover, we identified the adipokine Adiponectin as a key player in the beneficial effects of EE. We reported that increased levels of Adiponectin in the brain led to microglia phenotype and activation state regulation, thus reducing global brain inflammation in mice. Indeed, the anti-inflammatory and antidepressants effects of EE are abolished in Adiponectin deficient mice. We demonstrated that anti-inflammatory actions of Adiponectin on microglia is mediated through the Adiponectin Receptor 1. Those results highlight the key role of the adiponergic system in the treatment of psychiatric disorders. Therefore, we tested the effect of AdipoRon, a potent Adiponectin receptors 1 and 2 agonist on corticosterone-treated mice. AdipoRon successfully reversed the corticosterone-induced depression-like state in mice. AdipoRon exerted its pleiotropic actions on various systems including hippocampal neurogenesis, serotonergic neurotransmission and neuroinflammation, which can explain its antidepressant properties. Together, our findings bring insight into the beneficial effects of "positive" life experiences in depression and neuroinflammation, highlight the pivotal role of Adiponectin pathway and emphasizes that AdipoRon or other Adiponectin receptor agonist may constitute a promising novel antidepressant
14
Zychlinska, Magdalena. "Murine Model System for EBV-related Diseases." Diss., lmu, 2007. http://nbn-resolving.de/urn:nbn:de:bvb:19-73499.
15
Barnard, Amanda Louise. "A murine model for immunotherapy of melanoma." Thesis, King's College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298460.
16
Levison, Scott. "Characterization of a murine model of colitis." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/characterization-of-a-murine-model-of-colitis(4b966667-a763-4bcc-8896-7a157cf3d3dd).html.
Abstract:
Inflammatory bowel disease (IBD) represents a complex spectrum of gastrointestinal diseases. Incorporating Crohn's disease (CD) and ulcerative colitis (UC), IBD is characterised by recurrent and chronic inflammation, significant morbidity, and an increasing global prevalence. Scientific advances regarding the aetiology, pathogenesis and treatment of these relapsing immune-mediated diseases have developed in parallel to the study of experimental models of intestinal inflammation. The correlation of phenotype, histology and immune response with mucosal gene expression, permits the investigation of induced pathology for human translation. Trichuris muris (mouse whipworm) infection induces chronic colitis in susceptible strains (e.g. AKR). Chronic disease displays both a polarised CD4+ T-helper1 (TH1) immune response and histological, transmural colonic inflammation. Conversely, resistant mouse strains (e.g. BALB/c) exhibit transient infection and inflammation which quickly resolves under a presiding TH2 response. Work presented in this thesis investigates differential gene expression and biological pathways central to colonic outcome, and the genetic basis of chronic T. muris-induced colitis. This thesis demonstrates that the phenotypic and transcriptional profile of the T. muris model shared many similarities to widely used experimental models of colonic inflammation and to human IBD. Mice susceptible to chronic colonic inflammation displayed functional gene expression differences to those of resistant mice, including the up-regulation of pro-inflammatory, apoptosis and chemokine signalling pathway genes. Cellular homeostasis pathways and tight junction molecules were conversely down-regulated. Infected AKR demonstrated predominant TH1/ TH17 transcriptional activity, presenting this model as a platform to examine biological commonalities among chronic colitides. A Quantitative Trait Locus (QTL) study, performed by crossbreeding resistant and susceptible strains to T. muris infection, then identified key autosomal loci linked to chronic disease. Genes associated with known biological pathways, differential gene expression, and parental strain single nucleotide polymorphisms provided a novel and powerful strategy to reduce the number of candidate genes for further analysis. Of 7 T. muris (TM) QTL identified, 3 displayed overlap with other murine studies of parasite susceptibility. A separate locus, TM3, demonstrated overlap with published QTL in 3 unrelated experimental models of colitis and overlaid the Cdcs1 locus. TM3 possessed 33 significantly transcribed polymorphic genes (e.g. Ptpn22, Fcgr1, Rorc, Vcam1 and Vav3). Phenotypic pathway analysis, text mining and time-course qPCR all highlighted Vav3 (Human 1p13.3, murine Chr3 101.9 MB) as a key biological candidate in colitis susceptibility. As a final test of relevance to human disease, clinically proven IBD medications were administered to AKR mice post-T. muris infection, at a time-point when chronic disease was well established. Anti-TNFα Ab and corticosteroid therapy were shown to suppress TH1-driven experimental colitis, without affecting parasitic infection. Additionally, anti-TNFα Ab treatment was found to reduce pro-inflammatory macrophages yet preserve regulatory alternatively activated macrophage numbers within the colon. A previously unreported finding. Sharing biological commonalities with human CD, Trichuris muris colitis represents an advanced and tractable murine model for understanding the pathobiological mechanisms of chronic inflammatory disease. The key facet of this model is that despite identical injury some inbred mouse strains develop chronic colitis whilst others recover quickly and fully. The identification of differential mechanisms which govern outcome and a new platform to investigate novel targets of disease and disease therapy has implications for gastrointestinal inflammatory diseases and mucosal immunology.
17
Archelus, Anderson. "Rôle de l’environnement microbien dans la régulation de l’immunoglobuline A mucosale et dans le développement de la maladie de Berger." Thesis, Limoges, 2018. http://www.theses.fr/2018LIMO0007/document.
Abstract:
La maladie de Berger est la glomérulonéphrite la plus fréquente avec une estimation selon laquelle 1% de la population mondiale serait touchée. L’agent causal est une immunoglobuline (Ig)A anormale (polymérique et hypogalactosylée) qui se dépose dans le mésangium et provoque un dysfonctionnement rénal (protéinurie, hématurie) et des lésions glomérulaires. Dans 25% des cas, la maladie évolue sur 20 ans vers l’insuffisance rénale terminale. Des évidences, de plus en plus nombreuses, montrent que l’environnement microbien, en particulier bactérien, commensal ou pathogène, a un impact important sur le développement de la maladie. Au cours de ma thèse, j’ai d’abord étudié l’effet d’une molécule de la paroi bactérienne, le lipopolysaccharide (LPS), sur la production des IgA dans les muqueuses chez la souris normale. Les résultats que j’ai obtenus et ceux publiés permettent de proposer que la stimulation chronique des muqueuses par l’environnement microbien conduit à une augmentation de la production d’IgA néphrotoxiques, qui, du fait d’un déficit de leur récepteur pIgR mucosal, sont anormalement dirigées vers la circulation plûtôt que dans la lumière es muqueuses. Dans une seconde partie de mon travail, j’ai étudié l’effet du LPS sur le développement de la maladie de Berger dans un modèle de souris 1KI. Ces souris génétiquement modifiées produisent de l’IgA humaine et développent spontanément des dépôts mésangiaux d’IgA mais n’ont pas de protéinurie, d’hématurie ou de lésions glomérulaires. Nos résultats montrent que le LPS provoque une forte hématurie dans les souris 1KI lorsque celles-ci expriment le récepteur des IgA humaines, CD89, à la surface des polymorphonucléaires neutrophiles. En conclusion, mon travail de thèse a permis de mettre en lumière un impact de l’environnement microbien sur pIgR et sur les polymorphonucléaires neutrophiles dont la déficience ou l’activation pourrait contribuer au développement de la maladie de BergerIgA nephropathy is the most frequent glomerulonephritis worldwide. It features mesangial immunoglobulin (Ig)A deposits and proteinuria, hematuria and glomerular histological lesions. In 25% patients, it evolves, within 20 years, towards the end stage renal disease. Microbial environment, through the interaction with mucosa, is believed to play a crucial role in the development of the disease. The objectives of my work were to evaluate the effect of the microbial compound lipopolysaccharide (LPS) on the production of the nephritogenic IgA in the mucosa of mice and on the development of IgA nephropathy in the murine model 1KI that spontaneously develops mesangial IgA deposits without the other signs of the disease. Our results and those previously published suggest that the chronic stimulation of mucosa by microbiota leads to the increased production of nephritogenic IgA in the mucosa. These IgA, thanks to a deficient mucosal receptor pIgR in patients with IgA nephropathy, may be abnormally routed in the blood. We also showed that LPS provokes hematuria in the 1KI mice, when they express a specific IgA receptor, CD89, on the surface of polymorphonuclear neutrophils. Altogether our findings highlight the impact of microbial environment on pIgR and on polymorphonuclear neutrophils and thus, potentially, on IgA nephropathy
18
Helou, Doumet. "Rôle du facteur de transcription Nrf2 dans la régulation des fonctions du neutrophile in vitro et dans l’allergie cutanée." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS305/document.
Abstract:
Les neutrophiles constituent une première ligne de défense contre les agents infectieux. En revanche, leur activation incontrôlée peut exacerber certaines pathologies inflammatoires telles que les allergies cutanées. Notre équipe a montré précédemment que le facteur de transcription Nrf2 connu pour son rôle anti-oxydant, régulait l’inflammation cutanée dans l’hypersensibilité de contact (HSC). Ainsi ce travail a été mené pour évaluer in vitro l’implication de la voie Nrf2 dans les fonctions des neutrophiles et pour identifier son rôle dans le recrutement et l’activation des neutrophiles dans l’HSC.In vitro, nous montrons que la protéine Nrf2 est fortement exprimée dans les neutrophiles de la moelle osseuse. Nrf2 est fonctionnelle dans les neutrophiles stimulés : il active la transcription de gènes cibles cytoprotecteurs et diminue celle des gènes de l’inflammation. Ainsi, le prétraitement des neutrophiles avec un activateur de Nrf2 tel que le sulforaphane, réduit la production des formes réactives de l’oxygène (FRO)en réponse à une stimulation. En parallèle, l’absence de Nrf2 ne semble pas affecter la phagocytose et la nétose, deux fonctions clés du neutrophile. Enfin, Nrf2 est indispensable pour une migration optimale des neutrophiles en réponse aux chimiokines.Au cours de l’HSC induite par le dinitrochlorobenzène (DNCB), Nrf2 régule indirectement le recrutement des neutrophiles, en contrôlant le stress oxydant cutané et les voies inflammatoires impliquées dans la production de chimiokines, notamment CCL2, CCL4 et CCL11. En outre, Nrf2 induit l’augmentation d’expression du scavenger CD36 dans les macrophages et augmente ainsi leur capacité à éliminer les neutrophiles apoptotiques pour initier la résolution de l’inflammation.En conclusion, l’activation de Nrf2 dans les neutrophiles participe au contrôle de la production des FRO et la migration. En outre, Nrf2 émerge comme un effecteur clé dans le contrôle du recrutement et de la clairance des neutrophiles au cours de la réponse inflammatoire cutanée aux molécules allergisantes. La mise en évidence de ces mécanismes protecteurs de Nrf2 nous permet de proposer cette protéine comme nouvelle cible thérapeutique dans le contrôle d’inflammations cutanées chroniquesNeutrophils form the first line of defense against infectious agents. However, their uncontrolled activation may exacerbate certain inflammatory conditions such as cutaneous allergies. Our team has previously shown that Nrf2 transcription factor known for its antioxidant role, regulates skin inflammation in contact hypersensitivity (CHS). Thus, our work was carried out to evaluate in vitro the involvement of Nrf2 pathway in neutrophil functions and to identify Nrf2 role in neutrophil recruitment and activation in CHS.In vitro, we showed that the protein Nrf2 was highly expressed in bone marrow neutrophils. Nrf2 is functional in stimulated neutrophils: it activates the transcription of cytoprotective genes and downregulates that of inflammatory genes. Thus, pretreatment of neutrophils with an Nrf2 activator such as sulforaphane reduces the production of reactive oxygen species (ROS) in response to stimulation. In parallel, Nrf2 does not affect two key functions of neutrophil, phagocytosis and netosis.Finally, Nrf2 is essential for optimal migration of neutrophils toward chemokines. In CHS induced by the dinitrochlorobenzene (DNCB), Nrf2 indirectly regulates the recruitment of neutrophils, through regulation of skin oxidant stress and inflammatory pathways that are involved in chemokines production, including CCL2, CCL4 and CCL11. In addition, Nrf2 induces the up-regulation of scavenger CD36 in macrophages and thus increases their ability to eliminate apoptotic neutrophils leading to the resolution of inflammation.In conclusion, Nrf2 activation in neutrophils participates in the control of ROS production and migration. In addition, Nrf2 emerges as an important effector in the control of neutrophil recruitment and clearance during the skin inflammatory response to allergenic molecules. The demonstration of Nrf2 protective mechanisms leads us to suggest this protein as a new therapeutic target in the control of chronic skin inflammations
19
Nicolas, Sarah. "Mise en évidence du potentiel thérapeutique de l’adiponectine et de son rôle dans les effets antidépresseurs de l’environnement enrichi." Electronic Thesis or Diss., Université Côte d'Azur (ComUE), 2018. http://theses.univ-cotedazur.fr/2018AZUR4019.
Abstract:
La dépression est une pathologie multifactorielle induisant des troubles psychiques et physiques. De nouvelles thérapies visant à enrichir l’environnement des patients par des activités physiques, sociales et cognitives aident à la rémission en complément des traitements pharmacologiques. Cependant les bases moléculaires sous-jacentes aux bénéfices observés dans ces thérapies sont méconnues. C’est dans ce contexte que nous avons étudié les effets de ces thérapies via la mise en place d’un modèle murin d’environnement enrichi (EE). L’objectif de ma thèse a été d’évaluer les effets antidépresseurs de l’EE sur un modèle murin de dépression et d’identifier une nouvelle cible thérapeutique. J’ai montré que l’administration chronique de corticostérone induit un état dépressif et une neuroinflammation qui peuvent être réversés par l’EE. De plus, mes travaux ont mis en évidence, l'adiponectine (ApN), comme étant un acteur clef des effets de l'EE. J’ai montré que l’EE via l’ApN était capable de limiter la neuroinflammation. Par ailleurs, la caractérisation de souris n’exprimant pas l’ApN a montré que ces souris étaient insensibles en partie aux effets de l’EE. Par la suite, je me suis intéressée à la voie de signalisation de l’ApN impliquée dans ses effets anti-inflammatoires, j’ai montré que l’ApN inhibe l’activation de la microglie en se liant à son récepteur AdipoR1. Enfin, j’ai testé l’effet de l’AdipoRon, un agoniste des récepteurs de l’adiponectine, sur des souris traitées par la corticostérone. J’ai montré que l’AdipoRon réduisait l’état « dépressif » de ces souris. Mon travaille suggère que les effets antidépresseurs de l’AdipoRon sont dus à sa pléiotropie car il agit simultanément sur différents systèmes altérés dans la dépression dont la neurogenèse hippocampique, la neurotransmission sérotoninergique et la neuroinflammation. Pour conclure ce travail met en avant les effets bénéfiques de l’EE sur la dépression et la neuroinflammation. De plus, ils identifient l’ApN et sa voie de signalisation comme de nouvelles cibles prometteuses dans le traitement de la dépressionMajor depression is a complex disorder characterized by behavioral and cognitive impairments triggered by various factors including genetic predispositions, stress and environment. The pathophysiology of depression is poorly understood. Numerous evidence suggests that neuroinflammation is associated with depression. Alternative therapeutic strategies are needed and "positive" life experiences could be an efficient way to help the remission of the disorder. To study the potential antidepressant effects of such “positive” living conditions, we used the enriched environment (EE) paradigm on mice. The aim of our work was to fully characterize the antidepressant and anti-inflammatory effects of EE in a well-characterized murine model of depression-like behavior induced by long-term administration of corticosterone. We showed that EE efficiently reverses the anxiety/depression‐like state of mice and reduces neuroinflammation. Moreover, we identified the adipokine Adiponectin as a key player in the beneficial effects of EE. We reported that increased levels of Adiponectin in the brain led to microglia phenotype and activation state regulation, thus reducing global brain inflammation in mice. Indeed, the anti-inflammatory and antidepressants effects of EE are abolished in Adiponectin deficient mice. We demonstrated that anti-inflammatory actions of Adiponectin on microglia is mediated through the Adiponectin Receptor 1. Those results highlight the key role of the adiponergic system in the treatment of psychiatric disorders. Therefore, we tested the effect of AdipoRon, a potent Adiponectin receptors 1 and 2 agonist on corticosterone-treated mice. AdipoRon successfully reversed the corticosterone-induced depression-like state in mice. AdipoRon exerted its pleiotropic actions on various systems including hippocampal neurogenesis, serotonergic neurotransmission and neuroinflammation, which can explain its antidepressant properties. Together, our findings bring insight into the beneficial effects of "positive" life experiences in depression and neuroinflammation, highlight the pivotal role of Adiponectin pathway and emphasizes that AdipoRon or other Adiponectin receptor agonist may constitute a promising novel antidepressant
20
Carollo, Maria. "Investigation of chemokine receptor expression in an experimental model of chronic granulomatous inflammation." Thesis, Queen Mary, University of London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249652.
21
Koval, Lidia. "Investigating the effect of internal fixation stiffness on metaphyseal fracture healing in a mouse model." Thesis, Queensland University of Technology, 2014. https://eprints.qut.edu.au/75644/1/Lidia_Koval_Thesis.pdf.
Abstract:
This project examined the differences in healing of metaphyseal bone, when the implants of variable stiffness are used for fracture fixation. This knowledge is important in development of novel orthopaedic implants, used in orthopaedic surgery to stabilise the fractures. Dr Koval used a mouse model to create a fracture, and then assessed its healing with a combination of mechanical testing, microcomputed tomography and histomorphometric examination.
22
Bienvenu, Anne-Lise. "Neuroprotection et neuropaludisme des souris et des hommes." Thesis, Lyon 1, 2009. http://www.theses.fr/2009LYO10062.
Abstract:
Chaque année, au moins 300 millions de personnes sont touchées par le paludisme et plus d’1 million d’entre elles en décèdent. Le neuropaludisme reste une complication mortelle, notamment chez les jeunes enfants d’Afrique. En dehors de la résistance aux antipaludiques, un défi de la lutte contre le paludisme est de définir la place des traitements protecteurs de l’hôte associés aux antipaludiques. En effet, le taux de mortalité résiduelle au cours du neuropaludisme est d’environ 20%, malgré un traitement adapté. Ce travail décrit les modèles expérimentaux de neuropaludisme, la place des neuroprotecteurs dans cette pathologie, puis, l’efficacité de deux neuroprotecteurs, l’érythropoïétine recombinante et les statines, au cours d’un neuropaludisme expérimental. Enfin, la pertinence de la neuroprotection sera documentée par une étude de preuve de concept chez l’Homme en zone d’endémieThere are at least 300 million cases of malaria each year, resulting in more than a million deaths. Cerebral malaria is the most severe complication of malaria especially in young African children. Besides drug resistance, another challenge in the fight against malaria is the protective treatment of the host combined to the conventional antimalarial treatment. This opportunity came with the consideration of cerebral malaria residual case fatality rate of about 20%, despite a timely adequate antimalarial treatment. This work describes the available experimental model of cerebral malaria, the place of neuroprotective therapies in this disease and the efficacy of two neuroprotective drugs, recombinant erythropoietin and statins, during experimental cerebral malaria. Last, a proof-of-concept study documented the relevance of neuroprotection during human cerebral malaria in endemic area
23
Healy, D. M. "Comparative pathology of Lyssaviruses in a murine model." Thesis, Queen's University Belfast, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.546358.
24
Beer, Abigail J. "Development of an Inducible c-MYC Murine Model." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1602754882137456.
25
Gibbons, Peter Luke. "Development of a Pharmacodynamic Model of Murine Malaria." Thesis, Curtin University, 2015. http://hdl.handle.net/20.500.11937/1031.
Abstract:
The rational design of antimalarial therapies has historically been compromised by a paucity of pharmacodynamic data contributing to resistance through deployment of suboptimal doses. This thesis demonstrates a modified P. berghei murine malaria model for collecting detailed in vivo pharmacodynamic data and novel in silico mathematical model enabling optimisation of dosing and combination therapy. These models contribute to preclinical knowledge and provide the potential to assist in the development of methods to optimise clinical treatment.
26
Rebouças, Mônica Cardozo. "Resposta à quimioterapia com benzonidazol em camundongos com tríplice infecção por clones da cepa 21SF (São Felipe / Bahia) do trypanosoma cruzi." Centro de Pesquisas Gonçalo Moniz, 2012. https://www.arca.fiocruz.br/handle/icict/7162.
Abstract:
Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2013-10-16T19:49:06Z
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Monica Cardozo Rebouças. Resposta a quimioterapia...2012.pdf: 2111449 bytes, checksum: c4c3f7eeb987c9afdfca54d06568dd45 (MD5)Made available in DSpace on 2013-10-16T19:49:06Z (GMT). No. of bitstreams: 1 Monica Cardozo Rebouças. Resposta a quimioterapia...2012.pdf: 2111449 bytes, checksum: c4c3f7eeb987c9afdfca54d06568dd45 (MD5) Previous issue date: 2012
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil
Populações que residem em áreas endêmicas da doença de Chagas são submetidas a múltiplas infecções pelo Trypanosoma cruzi e podem estar infectadas com cepas ou clones com diferentes graus de virulência e susceptibilidade à quimioterapia. Este é um fator importante para o desenvolvimento e morbidade da doença. As cepas de Trypanosoma cruzi representam complexas populações multiclonais, homogêneas ou heterogêneas, com predominância de um clone principal. São biologicamente classificados em Biodemas (Tipos I, II e III) que apresentam diferentes graus de resistência à quimioterapia. Cepas do Tipo I são muito suscetíveis ao tratamento; cepas do Tipo II possuem uma média susceptibilidade (cepa 21SF); cepas de Tipo III são muito resistentes (cepa Colombiana). No presente estudo, é avaliado o resultado do tratamento de camundongos triplamente infectados com clones da cepa 21SF, em comparação com os infectados com a cepa parental. 50 camundongos foram infectados com a cepa 21SF (infecção única). O inóculo foi de 5 x 104 formas tripomastigotas sanguícolas. 80 camundongos foram infectados, sucessivamente, com 3 clones da cepa 21SF (C6, C7 e C8), inóculo: 1x104 formas tripomastigotas (infecção tripla). A infecção simples com cada clone também foi feita. Os camundongos de ambos os grupos foram divididos em dois subgrupos: tratados com Benzonidazol – BZ (100 mg/kg/dia - 60 doses) e controles não tratados. Após 60 dias do final do tratamento, os camundongos sobreviventes foram eutanasiados, por exsanguinação, pós-anestesia; o sangue foi coletado para o exame sorológico de imunofluorescência indireta; testes de cura foram realizados (parasitemia, xenodiagnósticos, hemocultura) e seções do coração e músculo esquelético foram coletadas, fixadas e processadas para o estudo histopatológico em cortes corados com Hematoxilina & Eosina. A PCR foi também usada como uma técnica diagnóstica complementar. Os testes parasitológicos mostraram uma positividade variando de 54,4% nos camundongos infectados com a cepa parental e tratados; 33,4 a 66,7% nos animais com infecção única pelos diversos clones e tratados e 26,7% nos camundongos com infecção tríplice, tratados. Os títulos sorológicos (TIFI) variaram de 1:20 a 1:280 nos infectados com cepa parental tratados com BZ e de 1:640 a 1:1280 para controles não tratados. Os títulos sorológicos na infecção única com cada clone variaram de 1:10 a 1:1280 em camundongos tratados e de 1:160 a 1:1280 nos controles não tratados. A PCR revelou positividade em todos os animais infectados, tratados. O resultado final foi obtido pela combinação dos testes parasitológicos com os títulos sorológicos revelando positividade de 6,6% nos camundongos infectados com a cepa parental e tratados; 0 a 18,2% nos animais com infecção única pelos diversos clones e tratados e 12% nos camundongos com infecção tríplice, tratados. Estudo histopatológico: Os camundongos infectados com a cepa parental apresentaram lesões que variavam de leves a moderadas, na maioria dos casos, predominante no miocárdio (animais tratados e controles não tratados) camundongos submetidos à infecção única por cada clone apresentaram lesões semelhantes aos demonstrados pela infecção com cepa parental. Os camundongos com infecção tripla apresentaram uma exacerbação de lesões, evoluindo para a miocardite crônica. Nestes casos, havia intensas lesões no músculo esquelético; animais tratados apresentaram uma nítida redução das lesões no miocárdio e no músculo esquelético. Os resultados da quimioterapia com Benzonidazol em animais triplamente infectados, considerando os testes parasitológicos e sorológicos, revelaram baixos índices de cura e agravamento das lesões tissulares nos camundongos submetidos a múltiplas infecções com clones obtidos da cepa 21SF.
People living in endemic areas of Chagas disease are submitted to multiple infections during their lives and could be infected with strains or clones with different virulence and susceptibility to chemotherapy. This is an important factor in the development and morbidity of the disease. Strains of Trypanosoma cruzi represent complex multiclonal populations, which can be homogeneous or heterogenous with predominance of a principal clone. The strains are biologically classified in different Biodemes (Types I, II and III) which disclose different degrees of resistance to chemotherapy. Type I strains are very susceptible to treatment; Type II strains disclose medium susceptibility (21SF strain); strains of Type III are very resistant (Colombian strain). The clones isolated from different strains can also present different degrees of resistance. In the present study the results of treatment of mice triple infected with clones of the 21SF strain is evaluated, in comparison with the infected with the parental strain. For the present study, 50 Swiss mice were infected with the 21SF strain (single infection).The inoculum was of 5 x 104 blood trypomastigotes. 80 mice were infected successively with 3 clones of the 21SF strain (C6, C7 and C8) inoculum: 1x104 trypomastigotes (triple infection). Single infection with each Clone was also done. The mice of both groups were divided into 2 sub-groups: treated with Benzonidazol –BZ (100mg/kg/day – 60 doses) and untreated controls. After 60 days of the end of treatment, surviving mice were killed by exsanguinations after anesthesia; the blood was collected for indirect immunofluorescence serological test; cure tests were performed (parasitemia, xenodiagnosis, haemoculture) and sections of the heart and skeletal muscle were collected, fixed and then processed for the histopathological study in sections stained with Hematoxilin end Eosin. PCR reaction was also performed in blood samples as a complementary diagnostic technique. Parasitological tests have shown positive results that varied from 54.4% for the group of mice infected with the parental strain and treated with BZ; 33.4 to 66.7% for the mice with single infection, with each clone, treated with BZ, and 26.7% with triple infection with the three clones, treated with BZ. Serology titers (IIFT) varied from 1:20 a 1:280 for the mice infected with parental strain treated with BZ and from 1:640 to 1:1280 for untreated controls. Serology titers in the single infection with each clone varied from 1:10 to 1:1280 in treated mice and from 1:160 to 1:1280 in the untreated controls. PCR reaction was positive in all the infected mice, treated. Parasitological tests combined with the sorological titers have shown a positivity of 6.6% for the mice infected with the parental strain and treated with BZ; 0 to 18.2% for the mice with single infection with each clone and treated an 12% for the mice with triple infection and treated with BZ. Histopathological examination revealed in mice infected with the parental strain, mild to moderate inflammatory lesions. Mice submitted to single infection with clones of the 21SF strain presented similar lesions to those determined by infection with parental strain. Mice with triple infection present an intensification of lesions, and evolution to a chronic myocarditis and intense lesions in skeletal muscle; Treated animals presented clear reduction of lesions in myocardium and in skeletal muscle. Results of chemotherapy with BZ in mice with triple infection with clones of the 21 SF T. cruzi strain, considering the results of parasitological and serological tests, revealed low cure rates and aggravation of tissue lesions in those animals submitted to triple infections with clones of the parental strain.
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Moore, Brioni R. "Pharmacodynamic studies of antimalarial drugs in a murine malaria model." Thesis, Curtin University, 2011. http://hdl.handle.net/20.500.11937/699.
Abstract:
Murine malaria models have proved to be a valuable preclinical tool, particularly in the development of new concepts in the research of human malaria. Plasmodium berghei (P. berghei), is the most extensively studied and manipulated rodent parasite and as a laboratory model, is largely selected for studies relating to developmental biology of parasites and investigation into new and innovative drug therapies. Whilst direct extrapolation from rodent biology to human malarias should be generally avoided, murine malaria models may contribute a greater understanding of important characteristics for antimalarial drug development and drug efficacy studies. However, there is currently a paucity of murine pharmacological data available for both commonly used, and emerging, antimalarial therapies. The findings of the studies in this thesis are seen as an important contribution to the preclinical knowledge of the investigated drugs which to date, have not been adequately studied.The aim of the thesis was to investigate the efficacy, pharmacokinetic and/or pharmacodynamic properties of various antimalarial drugs, in a P. berghei murine malaria model. Specific aims were to: (i) Evaluate the pharmacodynamic effects of dihydroartemisinin (DHA) in asplenic P. berghei infected mice. (ii) Investigate the pharmacokinetic and pharmacodynamic properties of single dose piperaquine (PQ) in healthy and P. berghei infected mice. (iii) Investigate the extended antimalarial effect of PQ concentrating on drug efficacy, re-inoculation outcomes and parasite viability. (iv) Evaluate the pharmacokinetic and pharmacodynamic properties of single and multiple doses of chloroquine (CQ) in healthy and P. berghei infected mice.Using an asplenic model of P. berghei malaria, the efficacy of single doses of DHA (0, 10, 30 and 100 mg/kg) were evaluated in uninfected and P. berghei infected, intact and asplenic mice. Haematology, liver biochemistry and histopathology were performed to investigate the responses of key organs to malaria infection. Whilst overall efficacy of single dose DHA in asplenic mice was shown to be similar to intact mice, the rate of parasite recrudescence after parasite nadir (20 h at all doses studied) was significantly higher in the asplenic mice, particularly at higher doses (30 and 100 mg/kg DHA). Histopathology of the liver and associated blood chemistries, demonstrated an increased stimulation of liver function during malaria infection in asplenic mice, when compared to intact mice.Whilst studying the pharmacokinetic and pharmacodynamic responses of PQ in the P. berghei malaria treatment model, particular focus was placed on (i) pharmacodynamic properties of single doses of PQ (0, 10, 30 and 90 mg/kg PQ phosphate (PQP)); (ii) pharmacokinetic parameters of PQ in healthy and P. berghei infected mice; (iii) efficacy of combined doses of 10 mg/kg PQP and 30 mg/kg DHA. Single dose administration of PQP resulted in a median survival time of 4, 10 and 54 days after doses of 0, 10 and 30 mg/kg PQP, respectively, while mice receiving a single 90 mg/kg dose showed a medium survival time exceeding 60 days (experimental endpoint). Pharmacokinetic analysis determined the elimination half-life of PQ in healthy and P. berghei infected mice was 18 and 16 days, respectively. Furthermore, extrapolation of PQ concentrations suggested that at 60 days the plasma drug concentration would be ineffective at suppressing the P. berghei infection (<10 μg/L). Combination of PQP and DHA resulted in a significantly lower parasite nadir (22 ± 12 fold) than for either drug given individually.Given that high dose PQP (90 mg/kg) demonstrated extended antimalarial efficacy, further invetsigations were pursued on drug efficacy, re-inoculation outcomes and parasite viability after a single 90 mg/kg dose of PQP. Investigation showed that after initial dosing, PQ concentrations were not adequate to suppress parasitaemia after 25 days. Furthermore, although viable parasites were present up to 90 days after drug administration, once these viable parasites were passaged into naive mice they were found to be generally resistant to PQ when exposed to the drug for a second time. Overall, PQ was found to have a substantial antimalarial effect in this model with this effect appearing to be sufficient for a host immunological response to be established thus resulting in the long term survival of P. berghei infected mice.Although CQ is widely used in preclinical animal studies, there is a paucity of comprehensive pharmacokinetic data of CQ in animal models. In this thesis robust pharmacokinetic and pharmacodynamic data of CQ is presentated after single and multiple dose administration of CQ in the P. berghei malaria model. The pharmacokinetics of desethyl-CQ (DECQ), the major active metabolite of CQ, were estimated. Pharmacodynamic data demonstrated that parasite nadir was reached 79 h after a single dose of 60 mg/kg CQ, with all mice developing parasite recrudescence. Multiple dose (5 x 50 mg/kg CQ; dosed every 24 h) administration resulted in parasitaemia falling below the limit of detection. Despite a short period of recrudescence (between 10 and 24 days after initial dose), parasitaemia remained undetectable until the experimental end point (35 days after the initial dose). Pharmacokinetic analysis determined an elimination half-life of 46.6 h in healthy mice and 99.3 h in malaria-infected mice (single dose data; non-compartmental analysis). The mean rate of formation of DCQ from CQ was 0.63 ± 0.55 h-1 with a formation half-life of 1.7 ± 1.0 h.Consequently, the drug efficacy, pharmacodynamic and pharmacokinetic data included in this thesis demonstrates that the current P. berghei murine malaria treatment model can be used as a valuable preclinical conceptual tool for the investigation of antimalarial drugs such as DHA, PQ and CQ.
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Delhon, Laure. "Rôle d’ADAMTSL2 et FBN1 dans l’ossification endochondrale : étude des modèles murins mimant la dysplasie géléophysique." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB081/document.
Abstract:
La dysplasie géléophysique (DG) est une maladie rare qui appartient à la famille des dysplasies acroméliques. Cette pathologie est caractérisée par un retard statural, une brachydactylie, une raideur articulaire, une dysmorphie faciale, une peau épaisse, une atteinte bronchopulmonaire et une surcharge valvulaire cardiaque conduisant le plus souvent à une mort précoce dans les premières années de la vie. Deux modes de transmissions ont été identifiés. Le premier autosomique récessif est dû à des mutations dans le gène ADAMTSL2. Le second, autosomique dominant est dû à un hot-spot de mutations dans les exons 41 et 42 qui codent pour le domaine Transforming Growth Factor (TGF) β-binding protein-like domain 5 (TB5) du gène FBN1. FBN1 et ADAMTSL2 codent pour des protéines sécrétées de la matrice extracellulaire (MEC). FBN1 code pour la fibrilline-1, une composante des microfibrilles qui jouent un rôle dans la biodisponibilité du TGFβ. La protéine ADAMTSL2 fait partie de la famille des ADAMTS mais n’a pas d’activité enzymatique dû à l’absence de domaine catalytique. Sa fonction est encore inconnue. Cependant des partenaires d’ADAMTSL2 ont été identifiés par notre équipe : latent-transforming growth factor beta-binding protein 1 (LTBP1) et FBN1 qui sont directement impliqués dans le stockage de TGFβ. Récemment une autre protéine, FBN2, a aussi été découverte comme partenaire d’ADAMTSL2 (Hubmacher D et. al.). L’objectif de ma thèse était de comprendre le mécanisme physiopathologique de la DG, grâce à l’analyse de modèles murins. Un premier modèle murin pour la forme récessive de la DG appelé CreCMV; Adamtsl2f/f (ou KO) a été généré. L’analyse phénotypique de ces souris a montré un retard statural, des os longs courts, des extrémités courtes. Dans les plaques de croissance des os longs des souris mutantes, nous avons observé une désorganisation des colonnes chondrocytaires associée à une diminution de l’expression du collagène de type 10, marqueur de la différentiation des chondrocytes. L’analyse de la matrice extracellulaire des plaques de croissance a révélé une désorganisation structurale importante. Une diminution de la fibrilline-1 et de LTBP-1 a été observée ainsi qu’une augmentation de l’activation de la voie de signalisation TGFβ au niveau de la plaque de croissance des souris mutantes. Nous avons observé une désorganisation du réseau microfibrillaire sur des cultures de chondrocytes de souris mutantes. Ces résultats nous ont permis de suggérer que la protéine ADAMTSL2 est impliquée dans la structure du réseau microfibrillaire, lieu de stockage du TGFβ et de démontrer un rôle majeur d’ADAMTSL2 dans la régulation de la chondrogenèse. Afin d’étudier la forme dominante de la DG, le modèle FBN1TB5+/- a été généré. Il est issu d’un système knock-in avec une mutation dans l’exon 42 du gène fbn1 qui correspond au domaine TB5 de la fibrilline-1. Nos résultats ont montré une réduction de la taille des souris hétérozygotes et homozygotes en comparaison aux souris sauvages au stade P1 et P30. Au stade P1, nous avons observé des chondrocytes plus larges et une dérégulation des marqueurs de la chondrogenèse au niveau de la plaque de croissance des fémurs des souris hétérozygotes, ainsi que chez les souris homozygotes. De plus, nous avons observé une très forte mortalité des souris homozygotes vers l’âge de 2 ou 3 mois. Nous en avons conclu que des mutations domaine TB5 de la fibrilline étaient liées à un retard statural et donc que FBN1 avait un rôle majeur dans la chondrogenèseGeleophysic dysplasia (GD) is a rare disease, which belong to acromelic group. This pathology is characterized by short stature, brachydactyly, joint stiffness, thick skin, facial dimorphism, broncho-pulmonary insufficiency and cardiac disease which lead to an early death in the first years of life. Two mode of inheritance have been identified. The first one, autosomal recessive, is due to mutations in ADAMTSL2 gene. The second, autosomal dominant, is due to hot-spot mutations in exon 41-42 of FBN1 gene, which encode the Transforming Growth Factor (TGF) β-binding protein-like domain 5 (TB5) of the protein. FBN1 and ADAMTSL2 encode secreted proteins of the extracellular matrix (ECM). FBN1 encodes fibrilline-1, component of microfibrillar network, playing a role in the bioavailability of TGF- β. ADAMTSL2 protein belongs to ADAMTS family, but does not have enzymatic activity due to lack of catalytic domain. Its function remains unknown. However, ADAMTSL2 partners have been identified by our team: latent-transforming growth factor beta-binding protein 1 (LTBP1) and FBN1, which are directly implied in storage of TGF-β. Recently, another protein, FBN2, have been identified as an ADAMTSL2 partner (Hubmacher D et. al.). The aim of my study was to understand the physiopathological mechanism of Geleophysic dysplasia by analysing murine models. A first murine model for the GD recessive form, CreCMV; Adamtsl2f/f (KO), have been generated. Phenotypic analysis of these mice showed short stature and shorter long bones and extremities. In long bone growth plate of mutant mice, we observed disorganization of chondrocyte columns, associated with decrease of collagen 10 expression, marker of chondrocyte differentiation. Analysis of ECM in growth plate revealed strong structural disorganization. Decrease of FBN1 and LTBP1 and were observed with an overactivation of TGF-β pathway in growth plate of mutant mice. We observed disorganization of microfibrillar network in chondrocyte cultures of mutant mice. These results suggest that ADAMTSL2 protein is implied in structure of microfibrillar network, where is stored TGF-β, and demonstrate major role of ADAMTSL2 in chondrogenesis. In order to study dominant form of GD, mouse model FBN1TB5+/-, have been generated. The mice were obtained by knock-in system, with mutation in exon 42 of FBN1 gene. Our results showed short stature of heterozygous (HT) and homozygous (Ho) mice compared to wild)type mice, at stage P1 and P30. At stage P1, we observed larger chondrocytes and deregulation of chondrogenesis markers in growth plate of HT and Ho mice. Furthermore, we observed high mortality of Ho mice at 2-3 months. We concluded that mutations in TB5 domain of FBN1 were linked to short stature and thus FBN1 have major role in chondrogenesis
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Sanlaville, Amélien. "Rôle de la réponse immunitaire adaptative anti-tumorale dans l’induction de la transition épithélio-mésenchymateuse." Thesis, Lyon, 2016. http://www.theses.fr/2016LYSE1276.
Abstract:
Un enjeu majeur en cancérologie est de réduire le risque de développement métastatique et de rechute. La transition épithélio-mésenchymateuse (EMT), processus physiologique au cours de l'embryogenèse, est un mécanisme central de la carcinogenèse, contribuant de façon précoce à la transformation et la dissémination des cellules tumorales via l'inhibition de la surveillance cellulaire (apoptose et senescence) et l'acquisition de capacités migratoires et invasives. Une autre caractéristique des cancers est la capacité d'échapper à la réponse immunitaire, puissante barrière anti-tumorale. Mais les cellules tumorales entretiennent des relations complexes avec le système immunitaire. Alors que la propension de l'inflammation et des cellules immunitaires innées à favoriser le développement tumoral et l'échappement immunitaire, via l'induction de l'EMT et le maintien d'un microenvironnement immuno-suppresseur, a été bien étudiée, le rôle éventuel de la réponse immunitaire adaptative dans la promotion de l'EMT est quant à lui peu connu. Grâce au développement d'un modèle murin de lignée tumorale mammaire plastique surexprimant l'oncogène Her2/Neu, ce travail démontre in vivo la capacité des cellules tumorales à subir l'EMT, induite par la réponse immunitaire médiée par les lymphocytes T. La déplétion spécifique des lymphocytes T (LT) CD4 restaure le phénotype épithélial de la tumeur, indiquant que les LT CD4 médient une réponse immunitaire induisant l'EMT. En retour, l'EMT confère aux cellules tumorales la capacité de modeler l'immunité comme le recrutement de neutrophiles. Ce travail apporte un nouvel éclairage sur les interactions entre cellules tumorales et système immunitaireCurrent clinical challenge in many carcinomas is to reduce the risk of metastasis development and cancer recurrence. Epithelial-mesenchymal transition (EMT), a physiological process during embryogenesis, is a central mechanism in oncogenesis. EMT induction contributes to early transformation and dissemination through inhibition of cellular surveillance (apoptosis and senescence) and increased migrative and invasive behavior. Another necessary hallmark of cancer is the ability of tumor cells to evade immune surveillance, a powerful barrier against tumor progression. But cancer cells enjoy intricate relations with the immune system. Whereas inclination of inflammation and innate immune cells to favor tumor development and immune escape, via EMT induction and immunosuppressive microenvironment maintenance, has been well investigated, the role of adaptive immune response in EMT promotion is understudied. Based on the development of a plastic murine mammary tumor cell line model overexpressing Her2/Neu oncogene, this study demonstrate in vivo that tumor cells keep an epithelial phenotype in adaptive immunodeficient mice but undergo EMT under the pressure of T-cell mediated immune response, characterized by loss of epithelial EpCAM marker and acquisition of mesenchymal features and EMT transcriptomic signature. CD4 T cell depletion but not CD8 restores the epithelial phenotype of tumors, suggesting that CD4 T cells mediate an immune response that could lead ton EMT induction. In return, EMT confers the ability of tumor cells to shape immunity like intra-tumor neutrophil infiltration. This work shed a new light on interactions between tumor cells and immune system
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Luzzi, Keith J. "Quantification of metastatic inefficiency in a murine liver model." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/mq21109.pdf.
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Holland, T. W. C. "The pathogenesis of a murine model of rheumatoid arthritis." Thesis, University of Nottingham, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.330136.
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Davami, Mohammad Hassan. "Immunology of crytopsoridiosis : studies with a murine infection model." Thesis, London School of Hygiene and Tropical Medicine (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267888.
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Franklin, Sarah Louise. "The extracellular matrix in a model of murine scrapie." Thesis, University of Bristol, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.440256.
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Hynes, Ann Marie. "Investigating nephronophthisis using a novel murine and cell model." Thesis, University of Newcastle upon Tyne, 2014. http://hdl.handle.net/10443/2370.
Abstract:
Nephronophthisis (NPHP) is a major cause of pediatric renal failure. Currently there is little understanding of the aetiology of the disease. In order to identify the molecular events leading to NPHP, we have created a novel mutant mouse strain containing a truncating mutation in the Cep290 gene. Patients with mutations in CEP290 present with a ciliopathy phenotype that includes retinal dystrophy, cerebellum defects and NPHP. Characterisation of Cep290LacZ/LacZ mice confirms that they display all the features of the human condition. Microarray analysis of newborn kidney tissue was used to explore initiating events leading to NPHP. Ciliopathies have recently been associated with either disrupted Wingless integrated (Wnt) or sonic hedgehog (Shh) signaling. We show that mutant kidneys display abnormal Shh signaling in the absence of Wnt signaling abnormalities. Primary cell cultures of collecting duct (CDT) cells (isolated from Cep290LacZ/LacZ mice and wild-type litter mates crossed with the “immorto” mouse) were established and characterised. CDT cells expressed the mineral corticoid receptor (MR) and the epithelial sodium channel (ENaC) alpha subunit. The CDT cell lines formed epithelial layers and formed tubules when maintained in 3D culture media. Cep290LacZ/LacZ CDT cells displayed ciliogenesis abnormalities as well as abnormal spheroids with loss of lumen when grown in 3D culture. Pharmacological activation of Shh signaling (purmorphamine) partially rescues the spheroid and ciliogenesis defects in Cep290LacZ/LacZ CDT cells. This implicates abnormal Shh signaling in the onset of NPHP and suggests that targeted treatment of Shh antagonists have therapeutic potential.
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Rutter, Erica M., Tracy L. Stepien, Barrett J. Anderies, Jonathan D. Plasencia, Eric C. Woolf, Adrienne C. Scheck, Gregory H. Turner, et al. "Mathematical Analysis of Glioma Growth in a Murine Model." NATURE PUBLISHING GROUP, 2017. http://hdl.handle.net/10150/624455.
Abstract:
Five immunocompetent C57BL/6-cBrd/cBrd/Cr (albino C57BL/6) mice were injected with GL261-luc2 cells, a cell line sharing characteristics of human glioblastoma multiforme (GBM). The mice were imaged using magnetic resonance (MR) at five separate time points to characterize growth and development of the tumor. After 25 days, the final tumor volumes of the mice varied from 12 mm(3) to 62 mm(3), even though mice were inoculated from the same tumor cell line under carefully controlled conditions. We generated hypotheses to explore large variances in final tumor size and tested them with our simple reaction-diffusion model in both a 3-dimensional (3D) finite difference method and a 2-dimensional (2D) level set method. The parameters obtained from a best-fit procedure, designed to yield simulated tumors as close as possible to the observed ones, vary by an order of magnitude between the three mice analyzed in detail. These differences may reflect morphological and biological variability in tumor growth, as well as errors in the mathematical model, perhaps from an oversimplification of the tumor dynamics or nonidentifiability of parameters. Our results generate parameters that match other experimental in vitro and in vivo measurements. Additionally, we calculate wave speed, which matches with other rat and human measurements.
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Yahya, Mohd Danial. "Immunological studies of malondialdehyde in a murine lupus model." Diss., The University of Arizona, 1992. http://hdl.handle.net/10150/185941.
Abstract:
Malondialdehyde (MDA) is a highly reactive three carbon dialdehyde produced as a byproduct of polyunsaturated fatty acid peroxidation and arachidonic acid metabolism. MDA readily forms intermolecular or intramolecular cross-linkages with chemical groups on various molecules and alters both their physicochemical properties and immunogenicity. In vivo these changes may generate neoantigens that consequently can elicit an immune response involving antibody production and immune complex formation. In this study the possible role of an anti-MDA immune response in the pathogenesis of disease in lupus-prone MRL/lpr mice was investigated. Physicochemical alterations to mouse serum albumin (MSA) were characterized and reliable immunological assays were developed to measure this immune response. MDA readily bound to amino groups on MSA, formed epitopes in a dose-dependent manner and altered its antigenicity. The presence of a specific anti-MDA response in MRL/lpr was verified using an enzyme-linked immunosorbent assay (ELISA) and inhibition ELISA. The immune complex capture assay, using MDA-specific polyclonal antiserum as capture antibody, detected significantly higher levels of MDA-containing immune complexes in sera of MRL/lpr mice compared to non-lupus strains. A time course study showed that in comparison to anti-dsDNA antibodies, anti-MDA antibodies were produced earlier and in significantly higher levels. These antibodies were found predominantly in the complement-fixing IgG₂ₐ and IgG₂(b) subclasses. Levels of IgG anti-MDA antibodies and MDA-containing immune complexes were highest at 4 months age. Western blot analysis revealed the presence of a 100 kilodalton MDA-modified protein in sera of MRL/lpr mice at 3 and 5 months of age but not at 1 month. In sera from non-lupus MRL/+ mice the level of MDA-modification of serum proteins was considerably lower. Vitamin E treatment for up to 16 weeks did not significantly affect the anti-MDA response, MDA-containing immune complex levels nor modification of serum proteins by MDA. Immunohistochemical studies demonstrated the presence of MDA-containing immune complexes, IgG and complement deposition in renal glomeruli. This is the first demonstration of circulating MDA-specific antibodies, MDA-containing immune complexes and MDA-modified serum proteins in MRL/lpr mice. This response may contribute to disease pathogenesis in these mice via formation and subsequent tissue deposition of immune complexes containing anti-MDA antibodies and MDA adducts.
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Laprano, Nicola. "Metabolic alterations in a murine model of Barth syndrome." Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/9105/.
Abstract:
Barth syndrome (BTHS) is a rare monogenic disease characterized by cardiomyopathy, skeletal myopathy and neutropenia, caused by mutations in the Xq28 locus. Mutations in the locus result in the loss of function of the Tafazzin protein (Taz), a transacylase responsible for the final step in the production of mature cardiolipin (CL). CL is a fundamental component of the inner mitochondrial membrane, where it cooperates in the maintenance of membrane stability and in various cellular processes such as mitochondrial respiration, autophagy and reactive oxygen species sensing. Using a novel murine model of BTHS, we investigated the mitochondrial phenotype, the metabolic signature and the gene expression profile in the heart of Taz knockout (KO) mice. We identified extensive heart-specific changes in the structure and composition of the mitochondria accompanied by alterations of the metabolome and gene expression. The alterations are specific to the adult, so probably derive from a developmental process happening after birth. The alteration of the gene expression seems to indicate activation of the unfolded protein response, suggesting an effect of stress response pathways in the cellular processes which underlie Barth syndrome.
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Gouny-Doridot, Ludivine. "Rôle du facteur de transcription STOX1 dans la physiopathologie de la prééclampsie : apport d'un modèle cellulaire et d'un modèle murin de transgénèse additive." Phd thesis, Université René Descartes - Paris V, 2013. http://tel.archives-ouvertes.fr/tel-01015874.
Abstract:
La prééclampsie est une maladie fréquente de la grossesse, caractérisée par l'apparition de novo d'une hypertension et d'une protéinurie à partir de la 20ème semaine d'aménorrhée. Ces symptômes s'aggravent au long de la grossesse, conduisant éventuellement à la mort maternelle en l'absence de prise en charge médicalisée. La thérapeutique définitive l'extraction du placenta, et donc du fœtus, ce qui induit une importante prématurité iatrogène. Les causes restent mal définies, mais il est bien admis que des anomalies au niveau de la mise en place du placenta sont au cœur de sa physiopathologie. Un défaut d'invasion trophoblastique des artères spiralées utérines semble être une constante de la maladie. Des données épidémiologiques démontrent qu'il existe une forte composante génétique dans la prééclampsie, et en 2005, un clonage positionnel dans des familles hollandaises, aboutit à l'identification de STOX1 comme le premier gène lié à cette maladie. STOX1 code un facteur de transcription intervenant dans le contrôle de la prolifération et de l'invasion des trophoblastes. Dans notre laboratoire, l'étude de STOX1 a été initiée par surexpression dans des cellules de choriocarcinome humain (modèle de trophoblastes) suivie d'une analyse transcriptomique. Celle-ci a révélé que les altérations d'expression génique observées suite à la surexpression de STOX1 étaient significativement corrélées à celles trouvées dans des placentas prééclamptiques. La création de souris transgéniques exprimant la version humaine de STOX1 sous le contrôle d'un promoteur ubiquitaire a alors été entreprise. Mes travaux de thèse ont principalement consisté à caractériser le phénotype de ces souris. Nous avons décidé de croiser des mâles transgéniques avec des souris sauvages afin de limiter l'expression du transgène à l'unité fœto-placentaire. Ces souris sauvages développent au cours de leur gestation une hypertension sévère, et une protéinurie. Elles constituent donc un nouveau modèle de prééclampsie. De plus, nous avons observé des anomalies que l'on trouve également chez les patientes : une fibrose rénale, une élévation des taux sériques de facteurs pro-angiogéniques (le récepteur soluble du VEGF et l'endogline soluble). Ces souris ont également des marqueurs d'hypertrophie cardiaque, attestant de l'impact sévère de l'hypertension. Pour mieux comprendre comment STOX1 peut induire ce syndrome, nous avons étudié son impact dans le modèle cellulaire surexprimant STOX1 et nous avons pu montré une altération de la gestion du stress oxydatif et de la fonction mitochondriale. En conclusion, nous avons obtenu et caractérisé un modèle de prééclampsie sévère, le seul existant montrant un phénotype hypertensif très marqué et très précoce. Ce modèle est un outil puissant pour découvrir de nouvelles voies impliquées dans la physiopathologie de la prééclampsie, pour rechercher de potentiels marqueurs diagnostiques précoces, tester des approches thérapeutiques innovantes et explorer les mécanismes responsables des conséquences à long terme de la prééclampsie.
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Prasad, Rajeev. "Evaluation of the Aging Immune System Using a Mouse Model of Brucella Infection." Thesis, Virginia Tech, 2008. http://hdl.handle.net/10919/35820.
Abstract:
Aging is accompanied by dysregulated immune function resulting in increased susceptibility of the elderly to diseases caused by microbial pathogens. There exists a multitude of data suggesting decreased resistance of the elderly to a variety of intracellular pathogens but there is no data relating the effect of aging on the immune response against Brucella. To elucidate the mechanism of immune dysregulation in old, old and young DBA/2 and BALB/c mice were infected with wild-type B. abortus strain 2308. The old and young mice were also vaccinated with vaccine B. abortus strain RB51 over-expressing Cu-Zn superoxide dismutase (SOD) and then challenged with B. abortus strain 2308 to determine the effect of vaccination in old vs. young mice. Specific IgG1 and IgG2a response to Brucella antigens were also evaluated to determine the effect of aging on Th-specificity of the immune response against Brucella infection. The immune response in aged vs. young mice was further assessed using RT-PCR and cytokine antibody array to determine the type of T-helper response. The experimental results indicate that all mice, regardless of age, survived infection ranging from doses of 2 x 104 to - 2 x 108 CFU. Though the older DBA/2 mice had a higher organism burden after 1 week of infection, these mice cleared Brucella infection more efficiently (5 weeks post-infection) than young mice. Vaccination with strain RB51 over-expressing SOD provided significant protection in young DBA/2, young BALB/c and old BALB/c mice but not in old DBA/2 mice after strain 2308 challenge. The results also suggest that old mice produced a different magnitude of IgG1 and IgG2a response to bacterioferritin and SOD of Brucella. The data suggests that both Th17 as well as Th1 responses were accentuated in old mice as compared to young mice following infection with Brucella. How the Th17 and Th1 branches of immune system work together enabling old mice to clear Brucella better than young mice warrants future investigation.Master of Science
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Ratet, Gwenn. "Contributions à l’étude de l’échappement des leptospires au système immunitaire : mise en évidence chez la souris de la colonisation rénale chronique à l’aide de leptospires bioluminescents, et rôle de la lipoprotéine LipL21 dans l’échappement du peptidoglycane à la reconnaissance par les récepteurs Nods." Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015PA05T012.
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Alsharif, Ifat. "Etudes in vitro et in vivo de l'effet neuroprotecteur d'un peptide dérivé de la sélénoprotéine T, le PSELT, dans un modèle de la maladie de Parkinson." Thesis, Normandie, 2018. http://www.theses.fr/2018NORMR010/document.
Abstract:
Les maladies neurodégénératives telles que la maladie d'Alzheimer, la maladie de Parkinson et la maladie de Huntington sont des pathologies progressives qui affectent le système nerveux, conduisant à la mort de certaines cellules nerveuses. Toutes ces maladies se caractérisent par la perte progressive de neurones dans des régions plus ou moins localisées du système nerveux, entraînant des complications cognitives, motrices ou perceptives. La MP est caractérisée par une dégénérescence sélective et progressive des neurones dopaminergiques situés dans la substance noire pars compacta (SNc), et de leurs terminaisons nerveuses qui normalementlibèrent la dopamine dans le striatum. Bien que les causes exactes de la MP soient inconnues, de nombreuses études ont démontré le rôle important du stress oxydatif dans la dégénérescence des neurones dopaminergiques. D’ailleurs, un niveau élevé de radicaux libres est observé dans le cerveau de patients post-mortem. Ces observations suggèrent que les protéines qui jouent un rôle dans la protection des neurones contre les effets du stress oxydatif peuvent représenter des cibles thérapeutiques intéressantes. En effet, pour maintenir l'équilibre d'oxydo-réduction, les cellules recrutent plusieurs enzymes réductrices dont des membres de la famille des sélénoprotéines. Des résultats obtenus dans notre laboratoire ont montré que la sélénoprotéine T (SelT), une nouvelle sélénoprotéine identifiée dans les cellules nerveuses dans notre laboratoire, est fortement exprimée dans les conditions de dégénérescence des neurones suite à un stress oxydant, et exerce un rôle neuroprotecteur. Ce rôle est assuré par son site actif contenant une cystéine et une sélénocystéine. Le but de ce travail de thèse était de valider l’utilisation d’un peptide nommé PSELT contenant le coeur actif de la SelT en tant que traitement neuroprotecteur dans la MP. Le traitement des cellules de neuroblastome SH-SY5Ypar le peptide PSELT réduit significativement les niveaux des radicaux libres et stimule la survie cellulaire en inhibant l’apoptose. Le PSELT semble traverser la membrane plasmique pour exercer son effet. In vivo, l’administration intranasale du PSELT protège les neurones et les fibres dopaminergiques dans un modèle de la MP chez la souris traitée par le 1-méthyl-4-phényl-1,2,3,6-tétrahydropyridine (MPTP). Le peptide PSELT augmente le taux de la tyrosine hydroxylase et inhibe l’apoptose, ce qui aboutit à une amélioration des troubles moteurs induits par le MPTP chez les animaux. L’ensemble de ces résultats montrent pour la première fois qu’un peptide issu de la SELT, le PSELT, est capable de protéger les neurones dopaminergiquesin vitro et in vivo et d’améliorer l’activité motrice des animaux modèles de la MP, ouvrant la voie au développement d’une nouvelle thérapie de neuroprotection pour la MPRésumé en anglais non fourni
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Dawson, Janet. "Development and characterisation of a murine model of chronic inflammation." Thesis, Royal Veterinary College (University of London), 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.522191.
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Uno, Jennifer Kikue. "Bone Mineralization in a Murine Model of Inflammatory Bowel Disease." Diss., Tucson, Arizona : University of Arizona, 2006. http://etd.library.arizona.edu/etd/GetFileServlet?file=file:///data1/pdf/etd/azu%5Fetd%5F1650%5F1%5Fm.pdf&type=application/pdf.
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Cherelyn, Vella. "Coxsackie B4 virus infection of the pancreas - a murine model." Thesis, Queen Mary, University of London, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.281620.
45
Martin, Claire Adriana. "Mechanisms of arrhythmogenesis in a murine model of Brugada syndrome." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648347.
46
Fonseca, Cátia Isabel Correia dos Reis. "Vaccine Targets in a Murine Model of Renal Cell Carcinoma." Doctoral thesis, Instituto de Ciências Biomédicas Abel Salazar, 2007. http://hdl.handle.net/10216/7210.
47
Rose, Lisa. "Bioluminescence Imaging of Canine Osteosarcoma in an Orthotopic Murine Model." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429269876.
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Van, Andel Roger A. "The immunopathogenesis of clostridium piliforme evaluated in a murine model /." free to MU campus, to others for purchase, 1997. http://wwwlib.umi.com/cr/mo/fullcit?p9842572.
49
Fonseca, Cátia Isabel Correia dos Reis. "Vaccine Targets in a Murine Model of Renal Cell Carcinoma." Tese, Instituto de Ciências Biomédicas Abel Salazar, 2007. http://hdl.handle.net/10216/7210.
50
Souza, Ricardo Santos 1982. "Estudo biomecânico comparativo entre dispositivos de fixação de mini slings em modelo murino ex-vivo = Biomechanical study comparing fixation devices of mini slings in murine model ex vivo." [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/312988.
Abstract:
Orientadores: Paulo César Rodrigues Palma, Cássio Luís Zanettini RiccettoDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Introdução e hipótese: O implante de slings corresponde ao padrão atual de tratamento da incontinência urinária de esforço. Para sua eficácia, exigem um mecanismo de ancoragem adequado. O objetivo deste estudo foi comparar as características biomecânicas de sistemas de fixação de dois modelos de mini slings atualmente disponíveis no mercado (Ophira® e Mini Arc®) por meio de teste de tração uniaxial em modelo murino ex vivo. Materiais e Métodos: Os dispositivos de ancoragem dos mini sling foram implantados cirurgicamente na parede abdominal de 15 ratos divididos em três grupos de cinco animais. Estes grupos foram sacrificados de acordo com a data pós implante em 7, 14 e 30 dias. Na sequência, extraia-se em bloco a parede abdominal de cada animal contendo os dispositivos de fixação. Este material era submetido a teste de tração até o despreendimento do sistema de ancoragem a partir do tecido leito de implante. Foram determinadas a medida da carga máxima (N) e deformação total (mm) até a avulsão. Os resultados foram comparados por meio do teste t de Student e o valor de p 5% foi considerado significativo. Resultados: O sistema de fixação do mini sling Ophira® em comparação ao Mini Arc® exigiu maior carga máxima para avulsão do tecido abdominal nos 3 períodos avaliados com significância estatística: 7º dia, 5,14 ± 0,69 N versus 4,11 ± 0,81 N (p 0,037), 14º dia 10,64 ± 0,81 N contra 9,02 ± 0,54 N (p 0,001) e no 30º dia 18,76 ± 1,48 N versus 14,85 ± 1,28 N (p < 0,001), respectivamente. Quanto ao deslocamento ocorrido durante a tração, o Ophira® desenvolveu maior deflexão significante em todos os momentos avaliados: no dia 7, 11,14 ± 0,53 mm enquanto o Mini Arc® 7,89 ± 1,01 mm (p 0,001), no dia 14 15,80 ± 0,95 mm versus 12,49 ± 1,43 mm (p < 0,001) e no trigésimo dia os valores foram 23,95 ± 1,38 mm contra 18,24 ± 0,50 mm (p < 0,001), respectivamente. Conclusão: O dispositivo de ancoragem do mini sling Ophira® proporcionou melhor fixação à parede abdominal murina em relação ao do Mini Arc®. Este resultado foi mantido mesmo no período pós-operatório tardio
Abstract: Introduction and hypothesis: Slings are currently the standard treatment for stress urinary incontinence. To be effective, they require an adequate anchoring system. The aim of this study is compare the biomechanical features of fixation systems of two mini slings models currently available on the market (Ophira¿ and Mini Arc¿). Materials and Methods: Anchoring devices of each sling were surgically implanted in the abdominal wall of 15 rats divided into three groups of five animals. These groups are formed according to the date of post implant euthanasia on 7, 14 and 30 days. Each abdominal wall was extracted in block containing the mini sling fixation device and was submitted to a tensile strength test for measure the maximum load and total deflection until device avulsion from the tissue. The results were compared using Student test t and a 5% cut off was considered significant. Results: The Ophira¿ mini sling fixation system demanded a greater maximum load compared to the Mini Arc¿ for avulsion of abdominal tissue in 3 evaluation periods with statistical significance: 7th day, 5.14 ± 0.69 versus 4.11 ± N 0,81 N (p 0.037), on day 14 10.64 ± 0.81 N versus 9.02 ± 0.54 N (p 0.001) and on day 30 18.76 ± 1.48 N versus 14.85 ± 1.28 N (p <0.001), respectively. Regarding the displacement occurred during traction, the Ophira¿ has developed significant higher deflection at all times evaluated: on day 7, 11.14 ± 0.53 mm while the Mini Arc¿ 7.89 ± 1.01 mm (p 0.001), on day 14 15.80 ± 0.95 versus 12.49 mm ± 1.43 mm (p <0.001) and on day 30 the values were 23.95 ± 1.38 mm vs. 18.24 ± 0.50 mm (p <0.001), respectively. Conclusion: The Ophira¿ mini sling anchoring device provided better fixation to the host tissue site compared to the Mini Arc¿ device in rats. This outcome were maintained even in the late post operative period
Mestrado
Fisiopatologia Cirúrgica
Mestre em Ciências