MHC class 1 molecules in immunity against tuberculosis

描述（由申请人提供）：本提案描述了一个为期5年的培训计划，用于发展儿科传染病的学术生涯。主要研究者已在华盛顿大学完成儿科住院医师培训，目前正在同一机构进行传染病研究金培训的最后一年。该计划将扩大他目前的科学技能，并促进新的技能，这将提高他的职业发展。具体而言，该计划促进了研究结核病免疫反应的职业发展。迈克尔·贝文博士将指导主要研究者的科学发展。Bevan博士是免疫学教授，霍华德休斯医学研究所研究员，也是免疫学领域的世界知名领导者。他培养了许多博士后研究员和研究生，他们自己也成为各自领域公认的领导者。为了表彰这一杰出的记录，Bevan博士于2000年获得了美国免疫学家协会颁发的优秀指导奖。为了加强培训，该计划将争取博士大卫谢尔曼，病理学助理教授的专业知识。谢尔曼博士是一位分子微生物学家，在结核分枝杆菌（Mtb）的遗传操作方面具有丰富的经验。此外，一个由德高望重的科学家组成的咨询委员会将提供科学和职业建议。研究将侧重于了解CD8+ T细胞和MHC I类分子在结核病免疫保护中的作用。为了解决这些问题，建立了一种新的系统来监测小鼠气溶胶感染结核分枝杆菌后对结核分枝杆菌衍生抗原特异性T细胞的活性。肺结核将被确诊。该系统将使结核病免疫学中的一些最基本的问题能够比使用现有工具更精确地得到解决。具体目标包括：1）确定对Mtb衍生抗原特异性的CD4+和CD8+ T细胞在小鼠气溶胶感染后的位置、表型和功能，2）确定对Mtb衍生抗原特异性的CD4+与CD8+ T细胞在抗结核免疫中的作用，和3）确定MHC I类分子在调节涉及抗结核保护的免疫过程中的作用。除了提供有关结核病的重要信息外，这些实验还将揭示调节宿主防御的基本免疫机制。华盛顿大学儿科系传染病科通过在大学的任何实验室内倡导科学探索，为培训医生科学家提供了理想的环境。本提案中描述的培训计划，借鉴了几个跨部门的合作，将建立一个科学的利基为主要研究者，将他独特的定位为一个成功的学术生涯。

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the development of an academic career in Pediatric Infectious Diseases. The principal investigator has completed residency training in Pediatrics at the University of Washington and is currently in his final year of fellowship training in Infectious Diseases at the same institution. This program will expand upon his current scientific skills, and promote new skills that will enhance his career development. Specifically, this program promotes the development of a career studying the immune response to tuberculosis. Dr. Michael Bevan will mentor the principal investigator's scientific development. Dr. Bevan is a Professor of Immunology, a Howard Hughes Medical Institute Investigator, and a world-renowned leader in the field of immunology. He has trained numerous postdoctoral fellows and graduate students who themselves have become recognized leaders in their fields. In recognition of this outstanding record, Dr. Bevan received the Excellence in Mentoring Award from The American Association of Immunologists in 2000. To enhance the training, the program will enlist the expertise of Dr. David Sherman, Assistant Professor of Pathobiology. Dr. Sherman is a molecular microbiologist with considerable experience with genetic manipulation of Mycobacterium tuberculosis (Mtb). In addition, an advisory committee of highly regarded scientists will provide scientific and career advice. Research will focus on understanding the roles of CD8+ T cells and MHC class I molecules in immune protection against tuberculosis. To approach these issues, a new system to monitor the activity of T cells specific for Mtb-derived antigens after aerosol infection of mice with M. tuberculosis will be established. This system will enable some of the most fundamental questions in the immunology of tuberculosis to be addressed with greater precision than is possible using currently available tools. The specific aims include: 1) Determining the locations, phenotypes, and functions of CD4+ and CD8+ T cells specific for an Mtb-derived antigen after aerosol infection of mice, 2) Determining the roles of CD4+ vs. CD8+ T cells specific for an Mtb-derived antigen in immunity against tuberculosis, and 3) determining the role of MHC class I molecules in regulating immune processes involved in protection against tuberculosis. In addition to providing important information about tuberculosis, these experiments will shed light on basic immune mechanisms that regulate host defense. The Division of Infectious Disease in the Department of Pediatrics at the University of Washington provides an ideal setting for training physician-scientists by advocating scientific exploration within any laboratory of the university. The training program described in this proposal, which draws on several interdepartmental collaborations, will establish a scientific niche for the principal investigator that will position him uniquely for a successful academic career.