Integration of T Cell Receptor and Chemokine Signaling in Thymocytes

胸腺细胞中 T 细胞受体和趋化因子信号传导的整合

基本信息

批准号：
7781386
负责人：
Sharon Celeste Morley
金额：
$ 11.17万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7781386
关键词：
Actin-Binding Protein Address Advisory Committees Affect Autoimmune Diseases Autoimmunity Biochemical Biological Assay Biological Models Caring Child Child health care Childhood Communicable Diseases Dependence Development Diagnosis Environment Event Extracellular Signal Regulated Kinases Generations Histologic Image Immune response Immune system Immunologist Immunology In Vitro Infection L-Plastin Laboratories Lead Leukocytes MEKs Mediating Mentors Mentorship Microscopy Migration Assay Molecular Movement Mus Pathology Patients Physicians Play Positioning Attribute Predisposition Principal Investigator Process Protein Kinase C Receptor Signaling Regulation Research Research Personnel Research Project Grants Role Scientist Signal Transduction Signaling Molecule Specialist T-Cell Development T-Cell Receptor T-Lymphocyte Testing Thymocyte Development Thymocyte Selection Thymus Gland Time Transgenic Mice Universities Washington career cell motility chemokine chemokine receptor clinically relevant enhanced green fluorescent protein improved in vivo migration programs skills thymocyte two-photon

项目摘要

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.

描述（由申请人提供）：作为致力于改善儿童健康的医师科学家，候选人旨在建立独立的研究职业，调查T细胞开发和法规的中断，从而导致对感染或自身免疫的易感性。为此，圣路易斯华盛顿大学的候选人和她的导师保罗·艾伦（Paul M. Allen）建立了一个研究项目，涉及T细胞开发基础的分子机制。适应性免疫反应需要在胸腺发育过程中产生T细胞。阳性选择的过程对胸腺发育至关重要，并且取决于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阳性选择过程中被整合。我们已经开发了两个互补模型系统来检验该假设。 TCR转基因小鼠的产生缺乏信号分子蛋白激酶C？（PKC？）揭示了由于TCR信号传导减少而导致的阳性选择减少。缺乏肌动蛋白结合蛋白L-倍蛋白的TCR转基因小鼠的产生显示胸腺细胞运动降低了趋化因子。该应用的目的是定义PKC的分子机制？调节阳性选择，以研究效率低下的TCR信号是否会改变阳性选择引起的趋化因子运动的变化，并确定胸腺细胞运动减少是否会改变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以及圣路易斯华盛顿大学病理和免疫学系的丰富环境，以开发启动独立研究计划所需的技术技能和知识分子。在保罗·艾伦（Paul M. Allen）的指导下，杰出的免疫学家组装咨询委员会以及参加华盛顿大学的课堂和研讨会，候选人将能够从指导的职位过渡到独立的研究员。为了了解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小儿传染病专家提供护理。相关性：无法正确产生T细胞的患者，一种白细胞，患有对感染和自身免疫性疾病的敏感性增加。该研究项目旨在提高我们对如何生成T细胞的理解。这项研究的结果可以应用于其免疫系统中缺乏症以及自身免疫性疾病患者中缺乏症患者的诊断和管理。