Role of SLP-76 in Naive and Memory T Cell Function

描述(申请人提供)：成熟的T淋巴细胞可以根据以前与抗原的接触情况分为至少三个组。与幼稚细胞不同的是，效应性和记忆性T淋巴细胞以前曾遇到过，并通过与表达适当MHC分子沟槽中的特定抗原的抗原提呈细胞相互作用而被激活。很明显，通过这些T细胞亚群的T细胞受体刺激产生的信号在数量和质量上都是不同的。众所周知，接头蛋白对所有细胞中信号的整合都是至关重要的。SH2结构域含有76千道尔顿的白细胞蛋白(SLP-76)，是胸腺细胞发育和成熟T细胞功能所必需的。不幸的是，由于SLP-76表达在胸腺发育过程中的绝对依赖性，目前还没有遗传模型来研究SLP-76在正常选择的成熟T细胞中的功能；既不是幼稚的，也不是效应的，也不是记忆的表型。在原代小鼠T细胞中的研究表明，SLP-76蛋白在幼稚T细胞、效应T细胞和记忆T细胞中的表达水平不同，这表明不同功能表型的成熟T细胞对SLP-76表达的要求和特定的分子相互作用是不同的。为了解决这一假设，我建议建立SLP-76表达受外源性药物控制的小鼠。这些小鼠将被用于体内感染模型，以评估不同成熟阶段对SLP-76的需求。有条件表达SLP-76的小鼠将与具有突变形式的蛋白质的小鼠交配，以评估体内的结构/功能。这份提案描述了一项为期五年的培训计划，目标是成为一名学术背景下的独立调查人员。首席调查员已完成内科和肾脏病的临床培训以及免疫学的研究生培训。加里·科雷茨基博士将指导首席研究员的科学和职业发展。科雷茨基博士是免疫学和信号转导领域的领导者。他是宾夕法尼亚大学信号转导项目的主任，曾指导过许多学生和博士后研究员。除了科雷茨基博士，还成立了一个由内科科学家组成的顾问委员会，负责监督科学和职业发展。

DESCRIPTION (provided by applicant): Mature T lymphocytes can be divided into at least three groups based on previous encounter with antigen. In contrast to naive cells, effector and memory T lymphocytes have previously encountered and been activated by interaction with an antigen presenting cell expressing a specific antigen in the groove of an appropriate MHC molecule. It has become clear that the signal generated by stimulation through the T cell receptor of these sub-populations of T cells is quantitatively and qualitatively different. Adaptor proteins are known to be critical for integration of signals in all cells. The SH2 domain containing Leukocyte Protein of 76 kilodaltons (SLP-76) is essential for both thymocyte development and mature T cell function. Unfortunately, because of the absolute dependence of SLP-76 expression during thymic development, there are no genetic models to study the function of SLP-76 in normally selected mature T cells; neither naive, effector, nor memory phenotype. Studies in primary murine T cells have shown that the level of SLP-76 protein expression is different in naive, effector and memory T cells suggesting the hypothesis that the requirements for SLP-76 expression and the specific molecular interactions differ in mature T cells of different functional phenotypes. To address this hypothesis, I propose to generate mice in which expression of SLP-76 is controlled by the administration of exogenous drugs. These mice will be utilized in in vivo infection models to evaluate the requirements for SLP-76 at different maturational stages. Mice conditionally expressing SLP-76 will be mated to mice with mutant forms of the protein to evaluate structure/function in vivo. This proposal describes a five-year training program with the goal of becoming an independent investigator in an academic setting. The principal investigator has completed clinical training in Internal Medicine and Nephrology and graduate training in immunology. Dr. Gary Koretzky will mentor the scientific and career development of the principal investigator. Dr. Koretzky is a leader in the fields of Immunology and signal transduction. He is director of the Signal Transduction Program at the University of Pennsylvania and has mentored numerous students and post-doctoral fellows. In addition to Dr. Koretzky, an advisory committee of physician-scientists has been formed to oversee scientific and career development.