Bcr and PPARgamma as targets for transplant arteriopathy

University Of Rochester, Rochester NY

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the development of an academic career in transplant biology. The principal investigator is a heart failure/transplant cardiologist and through this program will expand upon his scientific and investigative skills. The proposal focuses on transplant arteriopathy the leading cause of long term morbidity and mortality following heart transplant. Experimental models have shown that following transplantation there is an inflammatory response involving monocytes, neutrophils and T lymphocytes. Histopathology of coronary arteries reveals intimal proliferation mediated largely by smooth muscle cell (SMC) proliferation and the deposition of collagen and other extracellular matrix proteins. The principal investigator's long term goal is to understand how transcription factors regulate SMC gene expression that contributes to transplant arteriopathy. Recent work in the sponsor's laboratory has shown that crosstalk between the transcription factors NF-KappaB and PPARgamma may play an important role in regulating SMC inflammation. Additional work from the sponsor's laboratory suggests that the serine/threonine kinase Bcr may regulate this crosstalk between NF-KappaB and PPARgamma . Three specific aims are proposed: 1) Examine the effect of Bcr knock down on PPARgamma transcriptional activation and NF-KappaB transcriptional activation. 2) Identify PPARgamma amino acids phosphorylated by Bcr kinase. 3) Define the role of Bcr/PPARgamma in regulating transplant arteriopathy. The cardiovascular research centers of the University of Rochester provide the principal investigator with an ideal setting for studying vascular biology. This project will train him in both signal transduction and mechanisms of transcriptional regulation. These approaches to discovering the pathogenesis of cardiovascular disease will be critical to understanding and developing new therapies for transplant arteriopathy.