KATP channel expression and localization in the progression of heart failure

University Of Iowa, Iowa City IA

Investigators

Linked publications & trials

Abstract

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