Modulation of Dendritic Cell Function by Cytomegalovirus

巨细胞病毒对树突状细胞功能的调节

• 批准号: 6718648
• 负责人: Jatin M Vyas
• 金额: $ 11.45万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6718648
• 关键词: MHC class II antigen; SDS polyacrylamide gel electrophoresis; T lymphocyte; antigen presentation; bone marrow; cell component structure /function; cell membrane; cytomegalovirus; dendritic cells; gene expression; genetically modified animals; immunoprecipitation; immunoregulation; laboratory mouse; polymerase chain reaction; transfection /expression vector; vaccinia virus; virus genetics; western blottings

DESCRIPTION (provided by applicant): The applicant details a five-year research career development program in immunology and infectious diseases. The program will be conducted under the guidance of Dr. Hidde Ploegh in the Department of Pathology at the Harvard Medical School. The candidate has been dedicated to a career in basic science from his earliest training at Baylor College of Medicine and the NIAID, NIH. The applicant is clinically trained in Infectious Diseases and has long-term goals of answering fundamental questions regarding the subversion of the immune system by pathogenic microorganisms. The preliminary data demonstrate that mouse cytomegalovirus (MCMV) can be modified such that it expresses fluoresent proteins of interest. MCMV infects dendritic cells (DCs) and causes reduction of cell surface class II MHC molecules. Moreover, this data indicates that he possesses key skills in order to complete the research proposal. The proposed program includes coursework in virology and microbiology and training in microscopy for the first two years. The research component of the program focuses on the mechanisms employed by MCMV to manipulate the trafficking patterns of MHC products and formation of microdomains on the cell membrane of DCs. He seeks to understand the mechanisms involved in paralysis of DCs by MCMV. To this end, he has proposed the following specific aims: [1] Determine whether MCMV-infected DCs differ in their ability to process and present antigens to T cells. [2] Identify the MCMV genes involved in functional paralysis of DCs. [3] Determine whether MCMV interferes with the formation of tetraspan microdomains and location of CD63 and CD82 on the cell surface. Systematic study of MCMV will likely lead to insights into general principles of immune modulation by pathogenic viruses. In the latter phase of the five year period of support, the applicant will apply the approaches used for MCMV to the study of other pathogenic viruses relevant to human disease. Hence, the final specific aim is to determine whether vaccinia virus modulates the expression of class II MHC molecules and the formation of membrane microdomains on the cell surface of mouse bone-marrow derived DCs. The mentor and applicant have created an advisory committee to oversee the applicant's scientific progress and career development. The proposed program will allow the candidate to obtain the skills, knowledge and experience to become an independent investigator.

描述（由申请人提供）：申请人详细介绍了一项五年的免疫学和传染病研究职业发展计划。该计划将在哈佛医学院病理学系Hidde Ploegh博士的指导下进行。该候选人一直致力于他在贝勒医学院和NIAID的最早培训，从事基础科学的职业。申请人接受了传染病的临床培训，并且具有长期目标，即通过致病性微生物解决有关免疫系统颠覆的基本问题。初步数据表明，可以对小鼠巨细胞病毒（MCMV）进行修改，从而表达感兴趣的荧光蛋白。 MCMV感染树突状细胞（DC），并导致细胞表面II类MHC分子的降低。此外，这些数据表明他拥有关键技能以完成研究建议。拟议的计划包括病毒学和微生物学课程以及最初两年的显微镜培训。该计划的研究组成部分着重于MCMV采用的机制来操纵MHC产品的运输模式以及在DC的细胞膜上形成微域的贩运模式。他试图了解MCMV涉及DC瘫痪的机制。为此，他提出了以下特定目的：[1]确定感染了MCMV的DCS的处理能力是否有所不同，并将抗原呈现给T细胞。 [2]确定与DC功能瘫痪有关的MCMV基因。 [3]确定MCMV是否会干扰四面体微域的形成以及CD63和CD82在细胞表面上的位置。对MCMV的系统研究可能会导致对病原病毒免疫调节的一般原理的见解。在五年支持期的后期，申请人将将用于MCMV的方法应用于与人类疾病有关的其他致病病毒的研究。因此，最终的具体目的是确定离子病毒是否调节了II类MHC分子的表达以及在小鼠骨骼衍生的DC的细胞表面上的膜微区的形成。导师和申请人成立了一个咨询委员会，以监督申请人的科学进步和职业发展。拟议的计划将允许候选人获得成为独立研究者的技能，知识和经验。