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医生-科学家，候选人寻求建立一个独立的研究生涯，调查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，候选人和她的导师保罗M。位于圣路易斯的华盛顿大学的艾伦已经建立了一个研究项目，解决T细胞发育的分子机制。适应性免疫应答需要在胸腺发育期间产生T细胞。阳性选择过程对胸腺发育至关重要，并且依赖于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选择过程中被整合。我们已经开发了两个互补的模型系统来测试这一假设。产生TCR转基因小鼠缺乏的信号分子蛋白激酶C？(PKC?)显示了由于TCR信号传导减少而导致的阳性选择减少。产生TCR转基因小鼠缺乏肌动蛋白结合蛋白L-纤维蛋白原显示减少胸腺细胞运动趋化因子。本申请的目的是定义的分子机制，PKC？调节阳性选择，以研究无效的TCR信号传导是否改变由阳性选择诱导的趋化因子运动性的变化，并确定减少的胸腺细胞运动性是否改变TCR信号传导和阳性选择。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学和免疫学系的丰富环境，以发展启动独立研究计划所需的技术技能和智力严谨性。在Paul M的指导下，艾伦，杰出的免疫学家组成的咨询委员会，并参加在华盛顿大学的课程和研讨会，候选人将能够成功地从一个指导的立场过渡到一个独立的调查员。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患病儿童提供护理。 相关性：不能正常产生T细胞（一种白色血细胞）的患者，对感染和自身免疫性疾病的易感性增加。该研究项目旨在增加我们对T细胞如何产生的理解。这项研究的结果可以应用于诊断和管理患者的免疫系统缺陷，并可能与自身免疫性疾病的患者。

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.