MHC class 1 molecules in immunity against tuberculosis

描述(由申请者提供)：本建议书描述了一项为期5年的儿科传染病学术生涯发展培训计划。首席调查员已在华盛顿大学完成了儿科住院医师培训，目前正在该机构接受传染病研究员培训的最后一年。这项计划将扩大他目前的科学技能，并促进新的技能，将促进他的职业发展。具体地说，该计划促进了研究结核病免疫反应的职业发展。迈克尔·贝文博士将指导首席研究员的科学发展。贝文博士是免疫学教授，霍华德·休斯医学研究所研究员，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，他们本身也成为各自领域公认的领导者。为了表彰这一杰出的记录，贝文博士于2000年获得了美国免疫学家协会颁发的卓越导师奖。为了加强培训，该计划将征集病理生物学助理教授大卫·谢尔曼博士的专业知识。谢尔曼博士是一位分子微生物学家，在结核分枝杆菌(Mtb)的遗传操作方面拥有丰富的经验。此外，一个由备受尊敬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，将建立一种新的系统来监测结核分枝杆菌气雾剂感染小鼠后针对结核分枝杆菌来源抗原的T细胞的活性。这一系统将使结核病免疫学中的一些最基本的问题能够比目前可用的工具更精确地得到解决。研究的具体目标包括：1)确定结核分枝杆菌衍生抗原在小鼠气雾剂感染后的位置、表型和功能；2)确定结核分枝杆菌衍生抗原特异的CD4+和CD8+T细胞在抗结核免疫中的作用；以及3)确定MHC I类分子在调节参与抗结核病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，这些实验还将阐明调节宿主防御的基本免疫机制。华盛顿大学儿科的传染病部门倡导在该大学的任何实验室内进行科学探索，为培养内科科学家提供了理想的环境。这项建议中描述的培训计划利用了几个部门间的合作，将为首席研究人员建立一个科学利基，这将使他为成功的学术生涯奠定独特的地位。

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.