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，应聘者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细胞发育和调节的破坏。为此，这位候选人和她的导师、圣路易斯华盛顿大学的保罗·M·艾伦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。阳性选择过程是胸腺发育的关键过程，依赖于T细胞受体(TCR)信号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阳性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说。信号分子蛋白激酶C缺失的TCR转基因小鼠的产生？(PKC？)发现由于TCR信号减弱，阳性选择减少。缺乏肌动蛋白结合蛋白L-纤溶酶原蛋白的TCR转基因小鼠的产生显示胸腺细胞对趋化因子的动力减弱。本申请的目的是定义PKC？调节正选择，调查低效的TCR信号是否改变正选择诱导的趋化因子运动的变化，以及确定胸腺细胞运动减弱是否改变TCR信号和正选择。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和免疫学系的丰富环境来发展启动独立研究计划所需的技术技能和智力严谨。在著名免疫学家组成的咨询委员会保罗·M·艾伦的指导下，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指导职位过渡到独立研究人员。为了认识到正在进行的研究的临床相关性，候选人还将花费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：不能正确产生T细胞(一种白细胞)的患者，对感染和自身免疫性疾病的易感性增加。这项研究项目试图增加我们对T细胞是如何产生的理解。这项研究的结果可以应用于免疫系统缺陷患者的诊断和治疗，也可能应用于自身免疫性疾病患者的诊断和治疗。

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.