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The physiological and pathological regulation of apoptotic cell clearance /Kenyon, Karla. January 2007 (has links)
Thesis (Ph.D. in Immunology) -- University of Colorado Denver, 2007. / Typescript. Includes bibliographical references (leaves 177-196). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;
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Focal adhesion kinase signaling spatially regulates adhesion dynamics in fibroblastsIwanicki, Marcin P. January 2008 (has links)
Thesis (Ph. D.)--University of Virginia, 2008. / Title from title page. Includes bibliographical references. Also available online through Digital Dissertations.
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Studies of LRIG1 and the ERBB receptor family in breast and colorectal cancerLjuslinder, Ingrid, January 2009 (has links)
Diss. (sammanfattning) Umeå : Umeå universitet, 2009. / Härtill 5 uppsatser. Även tryckt utgåva.
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Regulation of G-protein gated inwardly rectifying potassium channels by tyrosine phosphorylation /Ippolito, Danielle Lorraine. January 2005 (has links)
Thesis (Ph. D.)--University of Washington, 2005. / Vita. Includes bibliographical references (leaves 137-167).
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Redox regulation of protein tyrosine phosphatases in cell membrane receptor-mediated signal transductionSalsman, Scott J. January 2005 (has links) (PDF)
Thesis (Ph. D.)--University of Oklahoma. / Bibliography: leaves 135-155.
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Utilização farmacológica de um composto inédito derivado de quinazolina como inibidor potencial da quinase de adesão focal (FAK) no processo de hipertrofia cardíaca em camundongo = Pharmacological use of a novel compound quinazoline derivative as potential inhibitor of the focal adhesion kinase in the process of cardiac hypertrophy in mice / Pharmacological use of a novel compound quinazoline derivative as potential inhibitor of the focal adhesion kinase in the process of cardiac hypertrophy in miceCardoso, Leandro, 1979- 07 June 2012 (has links)
Orientador: Kleber Gomes Franchini / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-20T23:08:02Z (GMT). No. of bitstreams: 1
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Previous issue date: 2012 / Resumo: Nas doenças do coração ocorre hipertrofia e remodelamento do ventrículo esquerdo com impacto negativo na evolução clínica. Esses fatores influenciam independentemente o risco cardiovascular por elevarem a predisposição a infartos do miocárdio, ao desenvolvimento de insuficiência cardíaca e ao aparecimento de arritmias ventriculares graves. Estruturalmente ocorrem crescimento e degeneração dos miócitos cardíacos, fibrose e alterações da microcirculação. Estas alterações comprometem irreversivelmente a histoarquitetura do miocárdio, limitando a eficácia dos tratamentos convencionais, principalmente no estágio mais avançado caracterizado pela insuficiência cardíaca. A rede de sinalização celular envolvida na resposta das células miocárdicas (miócito e não miócitos) a forças mecânicas tem papel crítico na compreensão da patogênese da hipertrofia. A quinase de adesão focal (FAK), uma enzima associada à sinalização por integrinas, é ativada precocemente e exerce influência no desenvolvimento e sustentação da resposta hipertrófica do miocárdio à sobrecarga pressórica. Nesse estudo foi avaliado o efeito de um composto inédito derivado de quinazolina (BZLO) com potencial ação inibitória da FAK no coração de camundongos submetidos à sobrecarga pressórica por coarctação da aorta. In vitro, esse composto inibiu a atividade catalítica da FAK purificada com IC50 de 1nM. In vivo, o tratamento dos camundongos submetidos à coarctação da aorta com o composto (BZLO) provocou inibição do resíduo Tyr397 da FAK. Demonstrando que o composto não só preveniu, mas também promoveu regressão da hipertrofia do ventrículo esquerdo típica do modelo, acompanhada de atenuação da hipertrofia dos cardiomiócitos e da fibrose intersticial, e preservação da função ventricular. Esses resultados indicam que o tratamento com o composto (BZLO), presumivelmente por inibir a FAK, atenua as alterações estruturais e funcionais provenientes da sobrecarga pressórica crônica no ventrículo esquerdo de camundongos, sugerindo seu potencial como alternativa na prevenção e tratamento da insuficiência cardíaca / Abstract: Cardiac remodeling and hypertrophy have negative impact in the evolution of heart disease. They raise predisposition to myocardium infarction, heart failure and fatal ventricular arrhythmias, being independent markers of cardiovascular prognosis. Cardiomyocyte growth followed by degeneration, interstitial fibrosis and alterations in the microcirculation can be detected structurally in hypertrophic hearts. These alterations jeopardize myocardium tissue architecture irreversibly limiting therapeutic efficacy especially in advanced stages of disease with heart failure. The understanding of signaling network in response to mechanical stimuli is crucial in the study of cardiac hypertrophy. Focal adhesion kinase (FAK) an enzyme linked to signaling by integrins is activated in response to pressure overload and influences the development of myocardial hypertrophic response. In the present study, a compound based on quinazoline scaffold which is a FAK inhibitor, named BZLO, is examined for its effects on cardiac hypertrophy of mice model of aortic constriction. BZLO strongly inhibits catalytic activity of purified FAK in vitro (IC50 = 1nM). Satisfactory bioavailability of BZLO was observed after oral administration. BZLO treatment decreased FAK phosphorylation at Tyr397 and attenuated cardiomyocyte growth and interstitial fibrosis preserving cardiac function in the mice model of chronic pressure overload induced by aortic constriction. These findings suggest that BZLO is effective in attenuating the deleterious structural and functional consequences of chronic pressure overload in mice heart, suggesting that it has the potential to be considered as an option for the prevention and treatment of heart failure / Mestrado / Fisiopatologia Médica / Mestre em Ciências
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Localização e função de quinase de adesão focal e Calsarcina-1 em cardiomiócitos de ratos = emprego de sondas moleculares e lentivírus / Localization and function of focal adhesion kinase and Calsarcin-1 in rat cardiomyocytes : using of molecular probes and lentivirusConsonni, Sílvio Roberto, 1986- 05 August 2015 (has links)
Orientador: Kleber Gomes Franchini / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-27T14:15:11Z (GMT). No. of bitstreams: 1
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Previous issue date: 2015 / Resumo: Há um crescente avanço no desenvolvimento das tecnologias que permitam a localização de proteínas em células por microscopias de luz e eletrônica combinadas, com o uso das sondas moleculares miniSOG e Apex2, por exemplo. Adicionalmente busca-se compreender como proteínas são responsáveis pelas funções celulares e teciduais. A Quinase de Adesão Focal (FAK), proteína da cascata de sinalização das integrinas é considerada uma mediadora em potencial do estresse mecânico nos cardiomiócitos. Sabe-se que em cardiomiócitos submetidos a estímulos hipertróficos, ocorre rápida ativação da FAK e sua redistribuição subcelular, contudo são pouco conhecidos os mecanismos envolvidos nesses processos. Outra proteína de grande importância no coração é a Calsarcina-1 (CS1), regulador negativo da via de Calcineurina, crucial no desenvolvimento da hipertrofia cardíaca. Entretanto os mecanismos envolvidos nessa regulação negativa, assim como a distribuição subcelular de CS1 são pouco conhecidos. Visando à interação entre essas áreas para estudo da distribuição espaço-temporal dos componentes celulares e de proteínas, bem como a importância da FAK e CS1 no sarcômero e seu papel na sinalização hipertrófica sob estímulo mecânico, o objetivo geral desse trabalho foi explorar a capacidade das proteínas FAK e CS1 para incorporar geneticamente sondas moleculares que permitissem monitorar por meio de imagens o comportamento dessas moléculas-chave na biologia do disco Z em MVRNs submetida ao estiramento mecânico. Para isso, foram realizados ensaios de localização subcelular com uso de sondas moleculares aplicadas à microscopia correlativa, bem como ensaios bioquímicos, moleculares e de atividade enzimática. Os dados confirmaram a FAK associada às fibras de actina e adesões focais em células H9c2 e foi demonstrado à microscopia de luz que FAK wild-type (wt) translocou-se parcialmente para o compartimento nuclear após estimulação do agonista fenilefrina, enquanto que FAK Y397F (forma mutante inativa) não apresentou mesmo fenótipo. Por outro lado, apesar da padronização e expressão das construções com FAK e miniSOG ou Apex2 em células HEK 293T e H9c2, não foi conclusiva a localização subcelular da FAK, por meio do uso de microscopia eletrônica em MVRN. Provavelmente devido à distribuição difusa da maior parte das moléculas de FAK, não foi identificada uma região elétron-densa conclusiva à microscopia eletrônica de transmissão. No tocante à importância da CS1, observou-se que o estiramento cíclico não induziu o aumento na expressão proteica ou gênica relativa de CS1 e CnA, assim como não houve alteração na atividade fosfatase de CnA. No entanto houve redução da interação de CS1 e CnA, bem como alteração na localização de CS1 em MVRN sob estímulo mecânico. Dados de superexpressão e silenciamento de CS1 corroboram a regulação negativa de CS1 à CnA em MVRN sob estímulo mecânico. Baseando-se em dados estruturais, especulou-se que como o sítio de ligação de NFAT e CS1 à CnA são muito próximos e ao mesmo tempo distante do sítio ativo da fosfatase, é possível que o papel de CS1 na regulação negativa de CnA ocorra por impedimento espacial ao fator de transcrição NFAT. Portanto, esses resultados podem contribuir para uma possível inferência farmacológica, visto que a via de Calcineurina-NFAT é uma das principais mediadoras de hipertrofia em cardiomiócitos, mediante estímulos patológicos / Abstract: There is an increasing move towards the development of technologies that allow the localization of proteins in cells by combined electron and light microscopy, with the use of molecular probes such as miniSOG and APEX2. Additionally we seek to understand how proteins are responsible for the cellular and tissue functions. The Focal Adhesion Kinase (FAK) is protein of integrin signaling cascade considered as a potential mediator of mechanical stress in cardiomyocytes. It is known that in cardiomyocytes subjected to hypertrophic stimuli by rapid activation of FAK and its subcellular redistribution, however the mechanisms involved in these processes are poorly understood. Another very important protein in the heart is Calsarcin-1 (CS1), a negative regulator of the Calcineurin pathway which is crucial in the development of cardiac hypertrophy. However the mechanisms involved in the negative regulation as well as the subcellular distribution CS1 are poorly understood. Aiming at the interaction between these areas to study the spatial-temporal distribution of cellular and protein components, and the importance of FAK and CS1 in the sarcomere and its role in hypertrophic signaling under mechanical stimulation, the aim of this study was to explore the ability of FAK and CS1 to incorporate genetically molecular probes that allow monitoring through images the behavior of these key molecules in the Z disc biology in MVRNs subjected to mechanical stretch. To this end, we performed subcellular localization assays using molecular probes applied to the correlative microscopy, biochemical and molecular assays and enzymatic activity. These data confirm the FAK associated with actin and focal adhesions fibers in H9c2 cells and has been shown by light microscopy that FAK wild-type (wt) is partially translocated to the nuclear compartment after stimulation of the agonist phenylephrine, while FAK Y397F (inactive mutant form) did not show the same phenotype. Moreover, despite standardization and expression of FAK and miniSOG or APEX2 in HEK 293T cells and H9c2, it was inconclusive subcellular localization of FAK, through the use of electron microscopy, in MVRN. Probably due to the diffuse distribution of most FAK molecules, it has no conclusive electron-dense region in transmission electron microscopy. Regarding the importance of CS1, it was observed that the cyclic stretch did not induce an increase in protein expression or gene relative CS1 and CnA, as there was no change in the phosphatase activity of CnA. However there was less interaction CS1 and CnA and change in CS1 location in MVRN under mechanical stimulation. CS1 overexpression and silencing corroborate the negative regulation of the CS1 over CnA in MVRN under mechanical stimulation. Based on structural data, it has been speculated that as the NFAT and CS1 binding sites are very close in CnA and at the same time distant from the active site of the phosphatase, it is possible that the role of CS1 in the negative regulation of CnA occur by steric hindrance to the NFAT transcription factor. Therefore, these results may contribute to a possible pharmacological inference, whereas Calcineurin-NFAT pathway is a major mediator of hypertrophy in cardiac myocytes by pathologic stimuli / Doutorado / Biologia Tecidual / Doutor em Biologia Celular e Estrutural
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The Role of ITK in the Development of Gamma Delta NKT Cells: A DissertationYin, Catherine C 08 August 2012 (has links)
The immune system is a complex network of interacting cells and tissues that is designed to protect the body from pathogens and other foreign substances. T cells are a major component of the immune system and consist of two distinct lineages distinguished by the expression of αβ or γδ T cell receptors (TCR). The Tec family kinase, Itk is an important mediator of signaling downstream of the TCR. Past studies on Itk has focused on how Itk regulates development, activation and differentiation of conventional αβ T cells and more recently how Itk regulates the development of innate-like αβ T cells. However, very little is known about the influence of Itk on γδ T cells. My studies show a previously unknown role for Itk in the development and function of γδ T cells. We report in the absence of Itk, γδ T cells were responsible for the spontaneously elevated levels of serum IgE and Itk-/- mice γδ T cells produced high levels of TH2 cytokines. Furthermore, there was an increase in γδ T cells specifically in the Vγ1.1+Vδ6.3+ (V6) subset that represents the dominant population of γδ NKT cells in Itk-/- mice. In addition, the V6 subset had increased expression of PLZF, a transcription factor normally required for αβ iNKT cell development. We further show that V6 cells develop and mature similar to αβ iNKT cells. Similar to defects previously seen in the terminal differentiation of Itk-/- αβ iNKT cell, V6 cells also had impaired maturation in the thymus in the absence of Itk. This data demonstrates a previously unknown role of Itk for the terminal maturation of V6 cells that has been shown to be the cell population that led to spontaneous dermatitis in mice. Given that drug companies have targeted Itk as a potential allergy drug due to Itk’s role in TH2 development and function, our data suggests that further studies on Itk are warranted.
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Monitoramento terapêutico de mesilato de imatinibe: relação entre níveis séricos e alcance de resposta molecular maior na leucemia mielóide crônica / Therapeutic drug monitoring of imatinib mesylate: relationship between serum levels and the molecular outcome (as determined by major molecular response) in chronic myeloid leukemiaRezende, Vinicius Marcondes 26 March 2018 (has links)
Dentre os vários tipos de leucemia, destaca-se a Leucemia Mielóide Crônica (LMC), um distúrbio mieloproliferativo em que ocorre a translocação entre o gene BCR no cromossomo 22 e o gene ABL1 no cromossomo 9. Essa translocação cria um cromossomo conhecido como Philadelphia (t 9,22)(q34;q11), ou Ph+, e a consequente formação de um produto único de proteínas BCR-ABL1. Essa proteína tem atividade de quinase constitutiva e impulsiona a proliferação descontrolada de células tronco hematopoiéticas. O surgimento de uma nova classe farmacológica no início dos anos 2000 - os inibidores de tirosina quinases, revolucionou o tratamento e o prognóstico da LMC, permitindo que esse câncer fosse tratado praticamente como uma doença crônica, com farmacoterapia oral. A droga de estréia dessa classe, o Mesilato de Imatinib, foi desenvolvida através de modelagem molecular para ser alvo-específica, mas apesar do desenvolvimento exitoso, após o início da comercialização, foram observadas falhas na ação em determinados pacientes. Há evidências de que a avaliação da relação entre a dose de imatinibe (e seus níveis sanguíneos) e a eficácia do tratamento medida através das respostas Hematológica, Citogenética e Molecular, seja uma forma de realizar o ajuste da dose reduzindo efeitos colaterais e custo do tratamento. No presente estudo foram avaliadas as concentrações séricas de imatinib, Cmin e Cmax, em 51 pacientes com Leucemia Mielóide Crônica, dos quais 33 atingiram Resposta Molecular Maior em até 12 meses de tratamento, 11 levaram mais que 12 meses para antingir, e 7 não atingiram. As concentrações séricas obtidas desses pacientes indicaram que no grupo que atingiu RMM em até 12 meses, os valores de vale (Cmin) se apresentaram com mediana de 889.2 ng/mL (721.9 e 1202.4 para primeiro e terceiro quartis respectivamente), sendo que o grupo que levou mais de 12 meses para atingir RMM, a concentração mediana observada foi de 611.0 ng/mL (493.0 e 816.0 para primeiro e terceiro quartis respectivamente), sendo essa diferença estatisticamente significativa (p < 0.05). Dessa forma demonstrou-se a importância do monitoramento das concentrações séricas de imatinib para o ajuste da dose e para a gestão do tratamento na mudança para segunda geração de inibidores de tirosina quinase. Através da análise comparativa dos dados populacionais estudados, observou-se não haver correlação significativa entre as concentrações séricas e índice de massa corpórea (IMC), peso, idade ou sexo / Among the various types of leukemia, Chronic Myeloid Leukemia (CML) stands out as a myeloproliferative disorder in which translocation occurs between the BCR gene on chromosome 22 and the ABL1 gene on chromosome 9. This translocation creates a chromosome known as Philadelphia (t 9,22) (q34; q11), or Ph +, and the consequent formation of a unique BCR-ABL1 protein product. This protein has constitutive kinase activity and drives the uncontrolled proliferation of hematopoietic stem cells. The launch of a new pharmacological class in the early 2000s - the tyrosine kinases inhibitors, revolutionized the treatment and prognosis of CML, allowing that cancer to be treated virtually as a chronic disease with oral pharmacotherapy. The newbie drug of this class, Imatinib Mesylate, was developed through molecular modeling to be target-specific, but despite the successful development, after the beginning of marketing, certain patients presented some failures in the response. There is an evidence that an assessment of the relationship between a dose of Imatinib (and its blood levels) and the efficacy of treatment from its Hematologic, Cytogenetic and Molecular Responses, is a really effective way to perform dose adjustment reducing side effects and cost of treatment. In the present study, the serum concentrations of Imatinib, Cmin and Cmax were evaluated in 51 patients with chronic myeloid leukemia, of which 33 reached major molecular response in up to 12 months of treatment, 10 took more than 12 months to achieve it, and 7 did not reach that. The serum concentrations obtained from those patients indicated that in the group that reached Major Molecular Response (MMR) within 12 months, the trough level (Cmin) presented a median of 889.2 ng / mL (721.9 and 1202.4 for first and third quartiles, respectively), and the group which took more than 12 months to reach MMR, the median concentration observed was 611.0 ng / mL (493.0 and 816.0 for the first and third quartiles respectively), and this difference was statistically significant (p < 0.05). Thus, the importance of monitoring serum imatinib concentrations for dose adjustment and treatment management in switching to second-generation tyrosine kinase inhibitors has been demonstrated. Through the comparative analysis of the population data, there was no significant correlation between serum concentrations and body mass index (BMI), weight, age or gender
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The Role of TEC Family Kinases in Innate T Cell Development and Function: a DissertationFelices, Martin 16 June 2008 (has links)
The Tec family kinases Itk and Rlk have been previously shown to have an important role in signaling downstream of the T cell receptor [TCR]. Almost all of the work done in the past on these two kinases looked at their role in conventional αβ T cells, specifically CD4+ T cells. These studies demonstrated functions for Itk [primarily] and Rlk in T cell development, activation, and differentiation. However, despite the wealth of knowledge on conventional CD4+ T cells, prior to the work presented here little to no studies addressed the role of Tec family kinases on CD8+ or innate T cell development. My studies show a clear role for Itk [and in some cases Rlk] in innate T cell development; whether it be deprecating, in the case of innate CD8+ T cells or some subsets of γδ T cells, or beneficial, in the case of NKT cells. I show that Itk has a crucial role in conventional CD8+ T cell development, as absence of Itk [or Itk and Rlk] causes strongly reduced numbers of conventional CD8+ T cells and a vigorous enhancement of an innate-like CD8+ T cell population. In NKT cells, my work demonstrates that Itk [and to a lesser extent Rlk] is required for terminal maturation, survival, and cytokine secretion. Finally, on γδ T cells Itk is important in maintaining the Th1 cytokine secretion profile usually associated with these cells, and regulating the development of CD4+ or NK1.1+ γδ T cells. Taken together, this work clearly illustrates an important role for Tec family kinases in innate T cell development and function.
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