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.
