The scientific theme of this Center is the cellular responses to stressors that result in cardiovascular disease. Despite the enormous impact of heart diseases that kill more than half a million Americans each year, the systematic studies of the effects of various factors contributing to heart disease at the molecular level are lacking. This COBRE will pioneer the studies of global gene expression in progression of heart disease leading to myocardial infarction using DNA microarray technologies. The rat ischemia-reperfusion model system will be developed by the Center. Our principal objectives are to identify genes whose expression responds to hypoxia (ischemia) and reoxygenation (reperfusion) and to construct a gene expression database for this model. We will use our gene expression database to develop testable hypotheses within each area of interest to Center investigators. The areas of expertise of COBRE investigators are diverse and individual research projects will be carried out at various levels, from molecular through organismal. In addition to DNA microarray technologies, a number of common methodological approaches will be used, including confocal microscopy, protein overproduction, and protein structure-fiinction analysis. Defects in the hypoxia sensing proteins, accumulated DNA damage, and defective DNA repair pathways have been linked to cardiac arrhythmias, ischemic neuronal damage, and hypertension. We propose to examine the mechanisms of hypoxia sensing and the structure of the PAS domain containing hypoxia sensors in prokaryotes and apply this knowledge to mammalian systems. The role of recombinational DNA repair pathways in the development of heart disease will be evaluated. Heat shock proteins, which appear to play an important role in protecting against cardiac damage caused by ischemia, also will be examined. The normal adaptive response of remaining myocardium surviving infarction is myocyte hypertrophy and reactive interstitial fibrosis. We propose to determine the nature and extent of hypertrophyinduced alterations in decorin-collagen interactions and collagen fibril architecture. Elevated salt intake is one factor contributing to development of hypertension and the progression of heart disease. We propose to identify the role of brain tachykinin neurotransmitters and in the control of salt intake and baroreflexes in normal and animal models of human essential hypertension. Collectively, the research proposals undertaken by this Center will elucidate cellular processes stimulated by stresses involved in the progression of cardiovascular disease.
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