Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 5 uppsatser.

Thesis (doctoral)--Karolinska Institutet, Stockholm, 1989. / Extra t.p. with thesis statement inserted. Includes bibliographical references.

Thesis (doctoral)--Karolinska Institutet, Stockholm, 1989. / Extra t.p. with thesis statement inserted. Includes bibliographical references.

No description available.

The development of T cells in the thymus is a tightly regulated process. Any defect in thymic differentiation could result in autoimmune disorders, inability to ward off infections or neoplasm. Early thymocyte development requires signals mediated through the preTCR complex by the associated CD3 chains (gamma, delta, epsilon, and zeta). Research conducted towards this project has revealed that signaling modules within the intracytoplasmic domain of CD3epsilon is absolutely required for this process. Interestingly, our results emphasized the importance of the proline-rich sequence motif in preTCR mediated signaling events, such as the proliferation of double negative thymocytes and the regulation of TCR surface expression on double positive thymocytes in a stage-specific manner. The outcomes of this project may provide a better understanding of the mechanism of preTCR-mediated thymocyte differentiation and the role of CD3 chains in these processes.

No description available.

Thesis (Ph.D. in Immunology) -- University of Colorado Denver, 2007. / Typescript. Includes bibliographical references (leaves 236-251). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 71-80).

Thesis (Ph. D.)--University of Washington, 2005. / Vita. Includes bibliographical references (leaves 92-100).

Orientador: Licio Augusto Velloso / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-15T14:17:03Z (GMT). No. of bitstreams: 1 Girasol_Alessandra_D.pdf: 2760832 bytes, checksum: a530db3fa7c6c0597b9212552bbcbb52 (MD5) Previous issue date: 2009 / Resumo: Muitos dos efeitos da leptina no sistema imune dependem de sua capacidade de modular a expressão de citocinas e a apoptose no timo. Surpreendentemente, alguns desses efeitos são dependentes de transdução de sinal através do IRS1/PI3-quinase, mas independentes da ativação da JAK2. Uma vez que todos os efeitos conhecidos da leptina em diferentes tipos celulares e tecidos parecem ser dependentes da ativação da JAK2, nós aventamos a hipótese de que, pelo menos para o controle da função tímica, outra quinase, até então desconhecida, poderia mediar a transdução do sinal da leptina através do ObR e pela cascata de sinalização do IRS1/PI3-quinase. Neste trabalho, mostramos que a tirosina quinase Fyn está constitutivamente associada ao ObR em células tímicas. Após um estímulo agudo por leptina, a Fyn é rapidamente fosforilada em tirosina, ativando-se e associando-se ao IRS1 de forma transiente. Todos estes efeitos são independentes da ativação da JAK2, e com a inibição da Fyn a transdução de sinal através do IRS1/PI3-quinase é abolida. Além disso, a inibição da Fyn modifica significativamente os efeitos da leptina sobra a expressão de citocinas no timo. Sendo assim, no timo, a Fyn atua como uma tirosina quinase que transduz o sinal da leptina independentemente da ativação da JAK2, e medeia alguns dos efeitos imunomodulatórios da leptina neste tecido / Abstract: Several effects of leptin in the immune system rely on its capacity to modulate cytokine expression and apoptosis in the thymus. Surprisingly, some of these effects are dependent on signal transduction through the IRS1/PI3-kinase, but not on the activation of JAK2. Since all the well known effects of leptin in different cell types and tissues seem to be dependent on JAK2 activation, we hypothesized that, at least for the control of thymic function, another, unknown kinase could mediate the transduction of the leptin signal from the ObR towards the IRS1/PI3-kinase signaling cascade. Here, we show that the tyrosine kinase Fyn is constitutively associated with the ObR in thymic cells. Following a leptin stimulus, Fyn undergoes an activating tyrosine phosphorylation and a transient association with IRS1. All these effects are independent on JAK2 activation and upon Fyn inhibition the signal transduction towards IRS1/PI3-kinase is abolished. In addition, the inhibition of Fyn significantly modifies the effects of leptin on thymic cytokine expression. Therefore, in the thymus, Fyn acts as a tyrosine kinase that transduces the leptin signal independently of JAK2 activation, and mediates some of the immunomodulatory effects of leptin in this tissue / Doutorado / Biologia Estrutural, Celular, Molecular e do Desenvolvimento / Doutor em Fisiopatologia Medica