This proposal describes a comprehensive 5-year training program for the career development of an academic clinician scientist in molecular and cellular cardiology. The principal investigator completed post- doctoral clinical and research training in Cardiovascular Medicine with clinical subspecialization in Advanced Heart Failure and Cardiac Transplantation at Johns Hopkins Hospital. Now an Assistant Professor at Temple University School of Medicine, the PI seeks additional research training in molecular and cellular electrophysiology and integrative cardiac physiology. The PI's long-term career goals are to gain original insight in the pathophysiology of heart failure, to identify novel targets for drug development, and to ultimately bring innovative therapies to clinical care. Her more immediate goals are to establish herself as a cardiac myocyte biologist. The candidate will study the role of the nitric oxide (NO) receptor soluble guanylyl cyclase (sGC) within the caveolae microdomain of cardiac myocytes in the pathophysiology of abnormal NO signaling in heart failure. She will pursue this research under the primary mentorship of cardiac physiologist Steven R. Houser, PhD, Chairperson of the Department of Physiology and Director of the Cardiovascular Research Center, and co-mentorship of caveolae biologist Victor Rizzo, PhD, Associate Professor of Anatomy and Cell Biology. A committee of senior researchers and physician-scientists will provide scientific and career advice. The PI has formulated a research strategy to determine the mechanism by which the loss of caveolae- localized sGC contributes to the pathologic signaling of NO and cyclic guanosine monophosphate (cGMP) in cardiac hypertrophy. Using a combination of genetic, molecular, cellular, immunohistochemical, electrophysio- logical, functional, and proteomic approaches, the PI will: 1) determine the functional implications of caveolae- localized myocardial sGC;2) characterize the molecular details of myocyte caveolae NO signaling relevant to the pathologic hypertrophy;and 3) determine the mechanism of sGC caveolae-localization. She will complement her molecular and cell biology research skills by learning techniques in cardiac myocyte electrophysiology, physiology, and functional proteomics--- all of which are vital to a cardiac myocyte biologist. The candidate will also enhance her career development with select coursework, seminars, national and international scientific symposia, and focused clinical activity in the advanced heart failure and transplantation program at Temple University Hospital. Research findings of this K08 are expected to provide new insights to the pathophysiology of abnormal NO signaling in heart failure, advance the understanding of the myocyte caveolae microdomain, and positively impact novel drug development for heart failure therapy. By the end of the award period, the PI will be well poised to launch a career as an independent, R01-funded clinician scientist and will apply the research skills obtained during the K08 towards studying other microdomains of myocyte signaling underlying the pathophysiology of heart failure.
Cardiac hypertrophy is a potent, independent risk factor for heart failure, a common clinical syndrome with increasing prevalence and high morbidity and mortality rates. Only those therapies that halt or partially reverse pathologic hypertrophy improve survival. Myocardial nitric oxide signaling is abnormal in cardiac hypertrophy and is therefore a viable target for novel heart failure therapy. This proposal will determine the mechanism by which a subset of the nitric oxide receptor soluble guanylyl cyclase, located within caveolae of cardiac myocytes, regulates cardiac function and protects against hypertrophy.
