This proposal describes a 5-year training program designed to develop an academic career for the candidate integrating transcriptional biology and cardiac electrophysiology. The research focuses on transcriptional regulation of ion channel expression in the heart during development and disease. The activities proposed rely on a collaborative program of study under co-supervision of two internationally recognized principal investigators, Drs. Mukesh K. Jain, an expert in molecular and cellular biology, and David S. Rosenbaum, an authority in cardiac electrophysiology. Together, the candidate will utilize both intellectual and proprietary resources from these laboratories with further guidance by an advisory committee of distinguished physicians and scientists. Participation in didactic courses and research seminars will enhance the educational success of the program. The mammalian ventricle exhibits a rich heterogeneity in expression of ion channels across the transmural surface. Electrophysiological heterogeneity under physiological conditions is proposed to synchronize the mechanical pump function, however, in pathological states enhanced heterogeneity underlies the substrate for malignant ventricular arrhythmias. The transient outward potassium current (Ito) is expressed heterogeneously across transmural surface, attributed to heterogeneous expression of KChlP2. The applicant has identified that Kruppel-like factor 15 (KLF15), a transcription factor in the heart regulates expression of KChlP2.
The specific aims of this proposal are to (1) elucidate the molecular basis for KLF15-mediated regulation of KChlP2 expression;(2) use voltage clamp techniques and high resolution optical imaging to elucidate the role of KLF15 in regulating electrophysiological function;and (3) determine the role of KLF15 as a transcription factor regulating electrophysiological heterogeneity in the canine heart. The Cardiovascular Research Institute and the Heart and Vascular Research Center at Case Western Reserve University provide extensive resources, collaborations, core facilities and intellectual expertise. As such, this is an ideal setting for the candidate to acquire mentored training towards an independent career as a physician-scientist.
Sudden cardiac death is the major cause of mortality in the USA and contributes to ~ 450,000 deaths annually.
This research aims to understand the genes that regulate electrophysiological function of the heart with the ultimate goal of finding new therapies to prevent / treat this devastating illness.
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