Bone Morphogenetic Proteins in Arterial Remodeling

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DESCRIPTION (provided by applicant): This Mentored K08 proposal describes a 5 year training program for Dr. Guzman's transition to scientific independence in the field of vascular biology. The candidate is an Assistant Professor in the Department of Surgery and Cell Biology. He will now expand on his scientific skills and knowledge base through a multidisciplinary interaction with Dr. Brigid L Hogan, a senior member of our Department of Cell Biology and Dr. Richard Hoover, from the Department of Pathology and the director of the Vanderbilt Vascular Biology Training Program. Dr. Guzman has also enlisted the help of an advisory committee of-highly-respected scientists who will provide scientific and career advice. They include Dr. Jeffrey Balser, Dr. Barbara Meyrick and Dr. Douglas Vaughan. The Department of Cell Biology provides an ideal environment for this training prograrn. It incorporates expertise from a broad array of disciplines and has extensive resources that can be used to support young faculty members. In addition to working directly in the laboratory of Dr. Hogan, Dr. Guzman will have a dedicated lab space that is located in close proximity to Dr. Hogan's lab and in a corridor of labs belonging to the Department of Cell Biology. Guzman has the full support of his Division Chief and Departmental Chair to devote 75 percent of his time to pursuing his academic research goals during the award period. Dr. Guzman's immediate goal is to obtain the training and experience necessary to become an independent scientist. The research plan focuses on the role of the Bone Morphogenetic Proteins (BMPs) in pathologic arterial remodeling. This family of extracellular signaling proteins belongs to the TGF-P superfamily and its role in vascular disease has not been characterized. The background and preliminary data suggest that these proteins may be important regulators of restenosis via their effects on vascular smooth muscle cell migration and proliferation. Based on his preliminary data, Dr. Guzman hypothesizes that BMP receptors may be ideal targets for gene-directed strategies to control intinial hyperplasia. The specific aims include: 1) Characterize the time course and cellular distribution of Bmp expression during pathologic arterial remodeling in mice. 2) Determine the role of shear stress in inducing endothelial BMP4 expression in-vitro. 3) Evaluate the effect of BMP type IA and IB receptor activation on injury-induced SMC proliferation and intinial accumulation in vivo. 4) Examine the effect of BMP type IA and IB receptor activation on SMC migration, invasion, and proliferation in vitro. In order to perform these specific aims, Dr. Guzman has outlined a research career development plan that includes a focused training period in the laboratory of Dr. Hogan along with course work in relevant areas. During this time he will learn to perform the techniques of in situ hybridization and double immunofluorescent staining. He will also learn fundamental techniques involved in the development of transgenic and knockout mouse strains. Dr. Guzman's long term goal is to make significant contributions to our understanding of pathologic arterial remodeling. It is expected that during this award period, Dr. Guzman will progress toward his goal of becoming an independent scientific investigator.