GENETIC DETERMINATION OF ALLOGRAFT VASCULOPATHY

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DESCRIPTION (Adapted from applicants' abstract) Dr. Benza will become an Assistant Professor of Medicine in April 1997, in the Division Cardiovascular Diseases (DCD) at the University of Alabama (UAB). Dr. Benza's subspecialty training is in the area of Cardiac Transplantation with a research interest in vascular biology. He has won several distinguished departmental awards for his research in endothelial cell-mediated fibrinolysis and has presented his research at several national and international meetings. He received an American Heart Association/Alabama Affiliate Award during his first year of fellowship to fund his work in endothelial cell-mediated fibrinolysis and has several publications in peer reviewed journals. His proposed studies will define the relationship between impaired fibrinolytic activity and the development of cardiac allograft vasculopathy (Tx CAD), a frequent and costly problem post transplantation. The premise of these studies is that the development of Tx CAD may be related to the presence of certain fibrinolytic protein (t-PA, PAI-1, u-PA) gene polymorphisms (FPGP) in both the donor graft and recipient. Specifically, the expression of these genes may be affected in a genotype-specific manner by certain factors (hypertriglyceridemia) which develop as a result of the transplant. This altered expression of fibrinolytic proteins (FPs) will then lead to fibrin deposition and the development of Tx CAD analogous to the development of native CAD. In this context, FPGPs for t-PA, PAI-1, u-PA and fibrinogen will be determined by Southern blot and PCR techniques for 150 donor/recipient pairs. These patients will then be followed for a period of 4 years to determine if these FPGP are predictive for the development of Tx CAD. In addition, plasma levels (recipient) and tissue levels (biopsy specimens) of FPs will be determined by ELISA and immuncytochemical fluorescent staining, respectively, to determine whether a link exists between the expression of these proteins, fibrinolytic genotypes and TX CAD. UAB, Department of Medicine and DCD will provide the research space, facilities, resources (secretarial support and office space) and appropriate time commitment (80%) to allow the candidate to conduct and accomplish the research goals set forth in this application. He will have no administrative or teaching duties during the period of this application. If his faculty mentor were to leave the institution, a new mentor will be appointed and his continued development toward becoming a independent physician scientist supported and encouraged.