The SCOR in Ischemic Heart Disease in Blacks at the Medical College of Wisconsin represents a multi-disciplinary proposal that focuses on solving basic (physiological, molecular, and genetic) and clinical (physiological and genetic) problems underlying this pathology. We have focused our efforts on diabetic heart disease, because this disease is of near epidemic proportions in the Black population, especially those with proven coronary artery disease, but they may also abrogate collateral growth in patients and augment the deleterious consequences of myocardial ischemia. Our program is composed of 4 Projects and 2 Core Facilities. Our strategy is to use experimental approaches that deviate from traditional methods to investigate the problems and to utilize corroborative experimental tools to test hypotheses at one level (documentation of physiological or pathophysiological responses) and then elucidate fundamental mechanisms at cellular, ion challenge molecular, and/or genetic levels. Projects 1 and 2 study mechanisms of coronary collateralization. Project 1, """"""""Integrative Analysis of Coronary Adaptations to Ischemia"""""""" will delineate the temporal sequence of expression of growth factors, and their respective receptors from the initiation to the final stages of collateralization in dogs. This project also elucidate the mechanisms by which diabetes compromises coronary collateral growth. Project 2 (Genetic Basis of Coronary Artery Disease and Coronary Collateralization) will define the genetic basis of coronary artery disease and coronary collateralization in Black and White patients. This project will also examine the familial transmission of alleles involved in coronary artery disease. In Project 3, """"""""Oxidant Stress and Human Coronary Microvascular Function,"""""""" the effects of diabetes on vascular function, vessels on vascular cells obtained from human hearts of Black and White patients. We will also utilize molecular strains of rats: Brown Norway, which are resistant to ischemia and Dah, which are sensitive to ischemia and Dahl, which are sensitive to ischemia (Project 4: """"""""Molecular Genetics of Cardioprotection""""""""). The Dahl strain is also insulin resistant and demonstrates salt sensitive hypertension. The two cores will be involved as repositories for data and administration, and data analysis. The Administration Core will contain a centralized file server for all results and will be accessible to all investigators. The Biostatistics Core will analyze all experimental results, and perform the association analyses of phenotype with genotype. We believe the science generated by this program will provide the template for rational pharmacological therapies to treat ischemic heart disease and will elucidate mechanisms contributing to ischemic heart disease in Blacks.
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