This revised proposal describes a 5-year training program for the development of an academic career in transplantation biology. The principal investigator has completed a research fellowship in transplantation biology. This program will afford the investigator resources to expand his research skills to develop into an independent investigator in transplantation immunology. David L. Perkins, M.D., Ph.D. will mentor the principal investigator's scientific development. Dr. Perkins is an established investigator with 20 years of research experience whose fellows have gone on to academic careers. The program will include the assistance of Gregory L. Stahl, PhD with expertise in Complement. An advisory committee of respected medical scientist will advise the investigator by providing scientific and career advice. The hypothesis is: Graft C1q provides crucial activating triggers via dendritic cells for the recipient T cell adaptive alloimmune response that mediates rejection. Research will focus on the role of Complement component C1q in transplantation graft rejection. Recent work by the Principal Investigator in Dr. Perkins's laboratory shows prolonged graft survival in Clq deficient transplants.
The specific aims i nclude: 1) Does C1q deficiency in the donor graft decrease recipient T cell responses? By application of in vivo cell trafficking via transgenic GFP mice to a murine model of heart transplantation in the absence of graft C1q, we will determine the effector function, activation, cytokine production and regulation of CD4 and CDS T cells infiltrating C1q deficient allografts. 2) Does C1q modulate dendritic cell activation and maturation following transplantation? Using a model of in vivo cell trafficking via transgenic GFP mice in murine heart transplantation in the presence or absence of graft C1q, we will determine if C1q is crucial component of the activation and maturation of dendritic cells. The location for this proposal, the Brigham and Women's hospital; provides an excellent setting and an established track record for the training of physician-scientists. The long-term goal is to train a physician-scientist that will succeed in the field of transplantation immunology.
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