Integration of T Cell Receptor and Chemokine Signaling in Thymocytes

描述（由申请人提供）：作为一名致力于改善儿童健康的内科科学家，候选人寻求建立一个独立的研究生涯，研究导致感染或自身免疫易感性的T细胞发育和调节的中断。为此，这位候选人和她的导师、圣路易斯华盛顿大学（Washington University in St. Louis）的保罗·m·艾伦（Paul M. Allen）建立了一个研究项目，研究T细胞发育的分子机制。适应性免疫反应需要在胸腺发育过程中产生T细胞。正向选择的过程对胸腺发育至关重要，并依赖于T细胞受体（TCR）信号传导和趋化因子介导的迁移。我们假设TCR和趋化因子受体信号在正向选择过程中是整合的。我们开发了两个互补的模型系统来检验这一假设。缺乏信号分子蛋白激酶C的TCR转基因小鼠的产生？（PKC?）显示由于TCR信号的减少，阳性选择减少。产生缺乏肌动蛋白结合蛋白l -活素的TCR转基因小鼠显示胸腺细胞对趋化因子的运动性减弱。本应用程序的目的是定义PKC？调节正选择，研究低效率的TCR信号传导是否改变了正选择诱导的趋化因子运动的变化，并确定胸腺细胞运动减弱是否改变了TCR信号传导和正选择。该研究项目将使候选人能够利用艾伦实验室的专业知识和圣路易斯华盛顿大学病理与免疫学系的丰富环境，培养启动独立研究项目所需的技术技能和智力严谨性。在由杰出免疫学家组成的咨询委员会Paul M. Allen的指导下，并参加华盛顿大学的课程和研讨会，候选人将能够成功地从导师的位置过渡到独立研究者的位置。为了保持对正在进行的研究的临床相关性的认识，候选人还将花一小部分时间作为儿科传染病专家为生病的儿童提供护理。

DESCRIPTION (provided by applicant): As a physician-scientist dedicated to improving the health of children, the candidate seeks to establish an independent research career investigating the disruptions of T cell development and regulation that lead to susceptibility to infection or autoimmunity. To this end, the candidate and her mentor, Paul M. Allen, at the Washington University in St. Louis, have established a research project addressing molecular mechanisms underlying T cell development. The adaptive immune response requires the generation of T cells during thymic development. The process of positive selection is critical to thymic development and is dependent upon both T cell receptor (TCR) signaling and chemokine-mediated migration. We hypothesize that TCR and chemokine receptor signals are integrated during positive selection. We have developed two complementary model systems to test this hypothesis. Generation of TCR transgenic mice deficient for the signaling molecule protein kinase C ? (PKC?) revealed diminished positive selection due to diminished TCR signaling. Generation of TCR transgenic mice deficient for the actin-binding protein L-plastin revealed diminished thymocyte motility towards chemokine. The aims of this application are to define the molecular mechanism by which PKC? regulates positive selection, to investigate whether inefficient TCR signaling alters the changes in chemokine motility induced by positive selection, and to determine whether diminished thymocyte motility alters TCR signaling and positive selection. This research project will enable the candidate to draw upon the expertise of the Allen laboratory and the rich environment of the Department of Pathology and Immunology at the Washington University in St. Louis to develop the technical skills and intellectual rigor required to launch an independent research program. With the mentorship of Paul M. Allen, the assembled advisory committee of distinguished immunologists, and participation in the classes and seminars at Washington University, the candidate will be able to successfully transition from a mentored position to an independent investigator. To remain cognizant of the clinical relevance of ongoing research, the candidate will also spend a small portion of her time delivering care to sick children as a specialist in Pediatric Infectious Diseases. RELEVANCE: Patients who cannot correctly produce T cells, a kind of white blood cell, suffer from increased susceptibility to infection and to autoimmune diseases. This research project seeks to increase our understanding of how T cells are produced. Results from this research could be applied to the diagnosis and management of patients with deficiencies in their immune system and possibly to patients with autoimmune diseases.