KATP channel expression and localization in the progression of heart failure

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This application describes a program of research and education to enhance the applicant's skills that will permit an independent career in investigation of molecular mechanisms of cardiac disease. The applicant has a background in electrophysiology and biophysics acquired through previous training, but requires additional theory and methodology in molecular biology, gene transfer, confocal microscopy and bioinformatics. This proposal is tailored to provide such training through execution of the scientific project under mentorship of a multidisciplinary advisory committee, as well as course work and seminars. The research component will investigate molecular mechanisms of cardioprotection in heart failure. Cardiovascular disease is the leading cause of mortality in the United States with 1 in 3 adults affected, thus presenting an enormous public health concern. Heart failure is the consequence of advanced disease and is present in approximately 5 million Americans, expected to increase as the population ages. Available therapies are often inadequate to treat or prevent progression of heart disease. Emerging data suggest membrane expression regulation of the cardioprotective ATP-sensitive potassium (KATP) channel plays a significant role in cardiac adaptation to stress. Preliminary results indicate that Ca2+/calmodulin dependent protein kinase II (CaMKII) inhibition increases KATP channel surface expression associated with resistance to ischemic injury. Preliminary results also indicate a role for the trafficking protein ankyrin-B in KATP channel membrane localization. Aim #1 will define the mechanism for regulation of KATP channel membrane expression level by CaMKII in normal and failing hearts while Aim #2 will determine the role in membrane localization of cardiomyocyte KATP channels by ankyrin-B in normal and failing hearts. Together, these aims will elucidate the relationship between the dynamics of KATP channel expression, CaMKII signaling and ankyrin-B membrane localization. Establishment of the molecular mechanisms underlying the regulation of KATP channel membrane expression and localization will identify potential therapeutic avenues for prevention and targeted interventions of mechanical and electrical dysfunction in heart failure. This scientific program in concert with the career development plan will provide the opportunity for the applicant to acquire additional skills needed to position her for an independent career as a successful physician-scientist.