Modulation of Dendritic Cell Function by Cytomegalovirus

描述（由申请人提供）：申请人详细描述了免疫学和传染病的五年研究职业发展计划。该项目将在哈佛医学院病理科Hidde Ploegh博士的指导下进行。这位候选人从他在贝勒医学院和美国国立卫生研究院的早期训练开始，就致力于基础科学的职业生涯。申请人接受过传染病方面的临床培训，其长期目标是回答有关病原微生物破坏免疫系统的基本问题。初步数据表明，小鼠巨细胞病毒（MCMV）可以修饰，使其表达感兴趣的荧光蛋白。MCMV感染树突状细胞（dc）并引起细胞表面II类MHC分子的减少。此外，这些数据表明他拥有完成研究计划的关键技能。该计划包括前两年的病毒学和微生物学课程以及显微镜学培训。该计划的研究部分侧重于MCMV利用的机制来操纵MHC产物的运输模式和dc细胞膜上微结构域的形成。他试图了解MCMV导致dc瘫痪的机制。为此，他提出了以下具体目标：[1]确定mcmv感染的dc在加工和向T细胞呈递抗原的能力上是否存在差异。鉴定与dc功能性瘫痪相关的MCMV基因。[3]确定MCMV是否干扰四跨面微结构域的形成以及CD63和CD82在细胞表面的定位。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。在五年资助期的后一阶段，申请人将把用于MCMV的方法应用于与人类疾病有关的其他致病性病毒的研究。因此，最终的具体目的是确定牛痘病毒是否调节小鼠骨髓源性dc细胞表面II类MHC分子的表达和膜微结构域的形成。导师和申请人成立了一个咨询委员会来监督申请人的科学进步和职业发展。该计划将使候选人获得成为独立调查员所需的技能、知识和经验。

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.