Defining the Unique Properties of the Distinct Signaling Machinery Used by the TCR

总体项目摘要/摘要 此申请是对正在进行的计划项目的续订的修订，其中五名调查人员与 不同但互补的专业知识已经合作了10年，以了解糟糕的特点 但TCR信号的根本重要方面。互动和协作产生的协同效应 取得了令人印象深刻的进展。该计划从互补的专业知识中受益匪浅， 来自结构生物学、蛋白质组学、免疫学、生物物理学、 成像和计算生物学。除了由每一家公司的独特专业知识创造的协同效应之外 调查人员和我们在过去10年中取得的进展，我们还利用了 蛋白质组学核心，扩展了我们在蛋白质组学方面的策略和分析技能。我们的合作研究 已经取得了相当大的进步和生产力。在这次修订中，我们所做的一个重大变化是 将项目数量从2个增加到4个，以便能够更充分地发展目标和 回答以下悬而未决的问题的方法：1)激酶的独特特征是什么 由TCR采用，已为调节关键的下游酪氨酸磷酸化和 配基识别所涉及的独特特性？2)电路的特性是什么 用于区分自身pMHC和激动剂-pMHC识别，以建立稳定的动态平衡状态 强健的细胞反应？3)适配器LAT缩合是如何调节的，并起到协调和 放大与强大的细胞反应相关的不同信号事件？4)TCR如何 信号网络调节RAS鸟嘌呤核苷酸交换因子(GEF)下游、规范和 以适当调节和忠实的方式向传入的TCR信号传递非规范的效应蛋白激酶信号？至 回答这些问题，一个新的项目现在被纳入到这项提案中，以解决每个问题。 我们的总体目标是充分利用我们目前的进步，利用我们独特的知识和技能。 与TCR信号相关，以更全面地了解分子、电路和 对TCR信号的调节，使能并确保适当的生物反应。

OVERALL PROJECT SUMMARY/ABSTRACT This application is a revision of a renewal of an ongoing Program Project in which five investigators with different but complementary expertise have worked together for 10 years to understand poorly characterized but fundamentally important aspects of TCR signaling. Synergy resulting from interactions and collaborations has yielded impressive progress. The Program benefitted enormously from the complementary expertise, skills and approaches by the 5 investigators from structural biology, proteomics, immunology, biophysics, imaging and computational biology. In addition to the synergy created by the distinct expertise of each of the investigators and the progress we have made over the previous 10 years, we also take advantage of a Proteomics Core that has extended our strategies and analytic skills in proteomics. Our collaborative studies have resulted in considerable progress and productivity. In this revision, a major change that we have made is an increase in the number of projects from 2 to 4 in order to allow for more fully developed aims and approaches to answer the following unanswered questions: 1) What are the unique features of the kinases employed by TCR that have been optimized for regulating critical downstream tyrosine phosphorylation and for unique characteristics involved in ligand discrimination? 2) What are the properties of the circuitry that allow for discrimination of self-pMHC from agonist-pMHC recognition to establish a stable homeostatic state versus a robust cellular response? 3) How is the adaptor LAT condensation regulated and serve to coordinate and amplify the diverse signaling events associated with a robust cellular response? 4) How does the TCR signaling network regulate Ras guanine nucleotide exchange factors (GEFs) with downstream, canonical and non-canonical effector kinase signals in a properly regulated and faithful manner to incoming TCR signals? To answer these questions, a new Project is now incorporated into this proposal to address each of these issues. Our overall goal then is to capitalize on our current progress and leverage our distinct knowledge and skills related to TCR signaling to more completely understand the distinct features of the molecules, the circuitry and the regulation of TCR signaling that enables and ensures appropriate biological responses.