DEATH RECEPTOR SIGNALING PATHWAYS IN T CELL DEVELOPMENT

我的研究目标是阐明凋亡信号通路在T细胞发育和稳态中的作用。为了实现这个目标，我已经生产出了转基因小鼠，其中这些途径的特定成分被阻断。 在一个转基因系中，一种被称为FADD的显性阴性形式的衔接分子在发育中的胸腺细胞和成熟的T淋巴细胞中表达。 FADD已被证明在某些神经生长因子-/肿瘤坏死因子-受体家族成员的连接后介导凋亡信号传导。 FADD的显性失活突变体（FADDdd）在触发这些受体后干扰死亡诱导。 令人惊讶的是，FADDdd转基因T细胞似乎在胸腺中经历正常的细胞凋亡，但在对抗原刺激的响应中具有缺陷的发育和减少的增殖。 这些自相矛盾的结果表明，控制死亡的机制也控制着生存和增殖。 此外，我的研究表明，这种控制是在细胞因子受体/Jak/Stat途径的水平上发挥作用的。 本文概述的研究将试图确定T细胞发育和稳态中这一过程的分子性质，并更广泛地确定死亡和多巴胺受体途径之间的相互作用。

The goal of my research is to elucidate the roles of apoptotic signaling pathways in the development and homeostasis of T cells. Toward this goal, I have produced transgenic mice in which specific components of these pathways have been blocked. In one transgenic line, a dominant-negative form of an adapter molecule known as FADD is expressed in developing thymocytes and mature T lymphocytes. FADD has been shown to mediate apoptotic signaling following ligation of certain nerve growth factor-/tumor necrosis factor-receptor family members. A dominant negative mutant of FADD (FADDdd) interferes with death induction following triggering of these receptors. Surprisingly, FADDdd transgenic T cells appear to undergo normal apoptosis in the thymus, but have defective development and reduced proliferation in response to antigenic stimulation. These paradoxical results suggest that the same mechanisms that control death also control survival and proliferation. Additionally, my research has demonstrated that this control is exerted at the level of the cytokine receptor/Jak/Stat pathway. The research outlined here will attempt to determine the molecular nature of this process in T cell development and homeostasis and to more broadly determine the interplay between death- and cytokine-receptor pathways.