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The research in my lab focuses on key signaling pathways involved in the development of transplant arteriopathy. Transplant arteriopathy is the leading cause of long term morbidity and mortality following heart transplantation. Histopathology reveals intimal proliferation. Animal models have shown that there is an early inflammatory response to transplant characterized predominantly by macrophage and lymphocyte accumulation within the graft. Subsequently intimal proliferation develops- an accumulation of smooth muscle cells and inflammatory cells. Recent studies have suggested that some of these intimal cells may be bone marrow precursor cells. The focus of our current research proposal is the role of peroxisome proliferator-activated receptors (PPARs) on the development of transplant arteriopathy. Peroxisome proliferator-activated receptors have been shown to exert anti-inflammatory activities in vascular and immunological cells including endothelial cells, vascular smooth muscle cells and monocytes. There are several different PPAR isoforms including PPAR-a, PPAR-g, and PPAR-b/d. We are utilizing cell culture data and animal models to assess the effect of peroxisome proliferator-activated receptors on the development of transplant arteriopathy. We hypothesize that absence of these receptors will worsen arteriopathy a disease initiated by inflammation, and treatment with PPAR agonists will attenuate arteriopathy. Our initial work will focus on PPAR g and the gene Bcr. Recent data from our laboratory suggest that Bcr acts as a modulator of vascular smooth muscle cell activation by decreasing PPARg transcriptional activity and enhancing NF-kB transcriptional activity. We are investigating the hypothesis that activation of PPARg and inhibition of Bcr will attenuate transplant arteriopathy. Positive results are likely to have important implications in the treatment of patients undergoing transplantation.
Advancing our understanding of the basic mechanisms responsible for normal and pathological function of the cardiovascular system.
