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

描述（由申请人提供）：成熟的T淋巴细胞可以根据以前与抗原的接触至少分为三组。与幼稚细胞相反，效应T淋巴细胞和记忆T淋巴细胞先前遇到抗原呈递细胞，并通过与抗原呈递细胞相互作用而被激活，抗原呈递细胞在适当的MHC分子的凹槽中表达特定抗原。很明显，通过这些T细胞亚群的T细胞受体产生的刺激信号在数量和质量上是不同的。已知接头蛋白对所有细胞中的信号整合至关重要。含有76千道尔顿白细胞蛋白（SLP-76）的SH2结构域对胸腺细胞发育和成熟T细胞功能至关重要。不幸的是，由于SLP-76在胸腺发育过程中的表达绝对依赖，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；既不是幼稚型，效应型，也不是记忆型。在小鼠原代T细胞中的研究表明，SLP-76蛋白的表达水平在幼稚T细胞、效应T细胞和记忆T细胞中是不同的，这提示了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，我建议产生SLP-76的表达由外源性药物管理控制的小鼠。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的小鼠将与具有该蛋白突变形式的小鼠交配，以在体内评估其结构/功能。该提案描述了一个为期五年的培训计划，目标是成为学术环境中的独立调查员。首席研究员完成了内科和肾脏病学的临床培训以及免疫学的研究生培训。Gary Koretzky博士将指导首席研究员的科学和职业发展。Koretzky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主任，并指导了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咨询委员会，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.