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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL094660-02
Application #
7816751
Study Section
Special Emphasis Panel (ZHL1-CSR-O (O1))
Program Officer
Carlson, Drew E
Project Start
2009-05-01
Project End
2014-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
2
Fiscal Year
2010
Total Cost
$129,060
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Jeyaraj, Darwin; Wan, Xiaoping; Ficker, Eckhard et al. (2013) Ionic bases for electrical remodeling of the canine cardiac ventricle. Am J Physiol Heart Circ Physiol 305:H410-9
Jeyaraj, Darwin; Scheer, Frank A J L; Ripperger, J├╝rgen A et al. (2012) Klf15 orchestrates circadian nitrogen homeostasis. Cell Metab 15:311-23
Jeyaraj, Darwin; Haldar, Saptarsi M; Wan, Xiaoping et al. (2012) Circadian rhythms govern cardiac repolarization and arrhythmogenesis. Nature 483:96-9
Haldar, Saptarsi M; Jeyaraj, Darwin; Anand, Priti et al. (2012) Kruppel-like factor 15 regulates skeletal muscle lipid flux and exercise adaptation. Proc Natl Acad Sci U S A 109:6739-44
Mahabeleshwar, Ganapati H; Kawanami, Daiji; Sharma, Nikunj et al. (2011) The myeloid transcription factor KLF2 regulates the host response to polymicrobial infection and endotoxic shock. Immunity 34:715-28
Liao, Xudong; Haldar, Saptarsi M; Lu, Yuan et al. (2010) Kruppel-like factor 4 regulates pressure-induced cardiac hypertrophy. J Mol Cell Cardiol 49:334-8
Lu, Yuan; Haldar, Saptarsi; Croce, Kevin et al. (2010) Kruppel-like factor 15 regulates smooth muscle response to vascular injury--brief report. Arterioscler Thromb Vasc Biol 30:1550-2
Haldar, Saptarsi M; Lu, Yuan; Jeyaraj, Darwin et al. (2010) Klf15 deficiency is a molecular link between heart failure and aortic aneurysm formation. Sci Transl Med 2:26ra26