This proposal is for a new K08 application which proposes a detailed plan for the candidate's research and a 4-year goal driven plan for further career development. The candidate's career goal is to become a successful independent scientific investigator. A career development plan is described that delineates the specific goals over the award period and the mechanisms that will be used to achieve them. Through didactic training and ongoing supervision through mentors and advisory committee, the candidate expects to 1) further develop as a basic science investigator, 2) conduct the proposed study with the highest degree of quality 3) present and publish studies in valvular heart disease at National conferences and leading journals 5) compete for advanced sources of funding and 6) develop insights in to the pathogenesis of valvular heart disease. The underlying mechanism for the pathogenesis of calcific aortic stenosis is unknown. This trend is becoming more pronounced with the aging population. Clinical studies indicate parallel risk factors for vascular atherosclerosis and aortic valve disease, the principle causative factor is elevated cholesterol levels. Due to these clinical observations, the PI has developed a translational approach to studying aortic valve disease. It is our hypothesis that calcification of the aortic valve is a direct result of valvular cellular transformation to an osteoblast phenotype that is initiated by hypercholesterolemia. The PI plans to test the hypothesis by the following specific Aims:
Aim 1 : Using the in vivo rabbit model, analyze the effects of hypercholesterotemia with and without statins in the atherosclerotic and proliferative aortic valve.
Aim 2 : Using the in vivo rabbit model, analyze the effects of hypercholesterolemia with and without statins in the calcification and mineralization of aortic valve.
Aim 3 : Using the in vivo rabbit model, determine the specific signaling pathways in the aortic valve which mediate the development of aortic valve atherosclerosis and osteoblastogenesis.
Aim 4 : Imaging the in vivo rabbit model of aortic valve disease. These studies provide the first in vivo model of aortic valve calcification which correlate the epidemiologic studies of atherosclerotic risk factors to the development of calcific aortic valve disease. If hypercholesterolemia stimulates the development of calcification in the aortic valve then the use of medical therapy such as HMG CoA reductase medications may have a role in the medical therapy of calcific aortic stenosis.
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