SIGNAL TRANSDUCTION FROM THE T CELL ANTIGEN RECEPTOR

描述：针对大多数外来病毒的免疫反应的产生 病原体或宿主来源的癌细胞严重依赖于 T细胞活化和增殖的初始阶段。激活T细胞 细胞的产生是因为TCR能够结合抗原肽 与主要组织相容性复合体编码的分子络合，以及 将这种细胞外刺激传递给细胞内信号 机械设备。从配体结合的TCR启动的信号涉及 Src家族(Lck、Fyn)和Syk家族(ZAP-70)的顺序激活 蛋白酪氨酸激酶(PTKs)。这些TCR调节的PTK，在Tm中， 催化磷酸化事件，导致激活 磷脂酶PLC-γ-L、RAS和磷脂酰肌醇-3激酶 (PI-3K)。尽管我们在理解上取得了令人瞩目的进步 TCR的功能近年来，这种受体的机制 偶联到下游信号蛋白，以及相关的贡献 在T细胞激活程序的这些蛋白质中，只有部分 明白了。 为了进一步定义TCR介导的信号转导过程，Dr。 亚伯拉罕的团队创造了一套新的细胞和分子 将允许应用强大的基因方法的试剂 受体后信号转导的几个关键成分分析 机械设备。人类T白血病细胞系Jurkat被选为 为拟议的研究建立了完善的基础模型体系。这个 TCR信令功能的主要读数将是一个原型 TCR参与的核反应，即IL-2基因 表情。建议项目的具体目标是：(1) ZAP-70的激活机制及该蛋白酪氨酸激酶的作用研究 以ZAP-70阴性Jurkat突变体为细胞的TCR信号转导 模型系统。(2)明确PLC-伽马-L的激活机制 通过TCR，并确定各种PLC的贡献-伽马-L 该酶在T细胞中的信号功能亚区 激活。(3)探讨PLC-伽马-L、RAS和PI-3K在细胞周期中的作用 以病毒来源的癌蛋白为靶点转录IL-2基因 T细胞中的多功能信号转导。

DESCRIPTION: The generation of immune responses against most foreign pathogens or host-derived cancer cells is critically dependent on an initial phase of T-cell activation and proliferation. Activation of T cells occurs because the TCR is able to bind antigenic peptides complexed with major histocompatibility complex-encoded molecules, and to relay this extracellular stimulus to the intracellular signaling machinery. Signal initiation from the ligand-bound TCR involves the sequential activation of Src family (Lck,Fyn) and Syk family (ZAP-70) protein tyrosine kinases (PTKs). These TCR-regulation PTKs, in tum, catalyze phosphorylation events leading to the activation of phospholipase PLC-gamma-l, Ras, and phosphatidylinositol-3 kinase (PI-3K). In spite of the impressive advances in our understanding of TCR function in recent years, the mechanism by which this receptor couples to downstream signaling proteins, and the relative contributions of these proteins to the T-cell activation program, are only partially understood. To further define the process of TCR-mediated signal transduction, Dr. Abraham's group has created a novel set of cellular and molecular reagents that will allow the application of powerful genetic approaches to analyses of several key components of the post-receptor signaling machinery. The human T-leukemic cell line, Jurkat, was chosen as a well-established base model system for the proposed studies. The principal readout for TCR signaling function will be a prototypical nuclear response to TCR engagement, i.e., interleukin-2 (IL-2) gene expression. The specific aims of the proposed project are: (1) To study the mechanism of ZAP-70 activation and the roles of this PTK in TCR signaling using a ZAP-70-negative Jurkat mutant as the cellular model system. (2) To define the mechanism of PLC-gamma-l activation by the TCR, and to determine the contributions of various PLC-gamma-l subdomains to the signaling functions of this enzyme during T-cell activation. (3) To examine the roles of PLC-gamma-l,Ras,and PI-3K in IL-2 gene transcription using a virus-derived oncoprotein as a polyfunctional signal transducer in T cells.