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SPECIALIZED CENTER OF RESEARCH IN HEART FAILURE


Biography

Overview
Heart failure is a leading cause of disability and death in the U.S. affecting at least 4.7 million individuals, with an estimated 400,000 new cases each year. Progress in the prevention and treatment of heart failure has been limited in magnitude due in some part to an incomplete understanding of basic biologic phenomena and mechanisms that underlie the clinical syndrome. This Heart Failure SCOR proposal attacks the problem across a spectrum of basic to clinical studies. The theme unifying these studies is that heart failure is a continuum of molecular phenomena and cellular mechanisms. These direct the progression from an underlying cause, such as a single nucleotide substitution in the DNA of an individual with familial dilated cardiomyopathy-to the multiple disturbances of cell and organ function and regulation that comprise the clinical syndrome of heart failure, irrespective of the initial inciting cause. The participating Project Leaders have an extensive record of produce collaboration and have focused their efforts on five interactive projects with substantial efforts of interface. Dr. C. Seidman's project seeks to identify genetic causes of inherited dilated cardiomyopathy with the expectation that during the next granting period a common theme will emerge that explains the significant genetic heterogeneity of this condition. Dr. (Michel) Project seeks to define the role of the interactions between caveolae and myocyte signaling proteins that evolve during the development and progression of heart failure. Project 3 (Ingwall) combines biophysical, biochemical and molecular biologic tools to test the hypothesis that decreased energy reserve via the creatine kinase system impairs contractile mutated G/a0 subunits that develop dilated cardiomyopathy with compensatory hypertrophy. These die of heart failure within two months. Pathways that link transgene expression to heart failure in these mice will be defined. Dr. Seidman's project has developed two genetically engineered lines of mice that are models of familial hypertrophic cardiomyopathy; these mice will be studied to determine those factors that worsen cardiac hypertrophy and in some, cause dilated cardiomyopathy and heart failure. All projects will interact closely with Core B (Mende and Lee), which has the technology to prepare and characterize contractile function of individual myocytes as well as to obtain non-invasive imaging of murine and human hearts to evaluate cardiac function. Cardiac histology, immunohistochemistry and in situ hybridization will be provided by CORE c (Schoen) to evaluate gene expression in the myocardium. In all of these interactive projects, the collaborating fundamental biological phenomena and mechanisms that bear on improved prevention and treatment of patients at risk. The aggregate productivity of coordinated project efforts has already exceeded the expectations of the individual components and we anticipate that these benefits will expand even further during the next granting period.
P50HL052320
SEIDMAN, CHRISTINE E.

Time
1995-01-15
2006-01-31
Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.