This proposal outlines a 5-year training plan designed to equip the applicant with tools that will foster his success as an academic investigator with a focus on translational heart failure (HF) research. He has completed rigorous clinical training in both internal medicine and cardiology and has spent the past two years acquiring experience in molecular cardiology in the mentor's laboratory. He is now poised for a career in academic medicine, and the proposed program offers an exceptional opportunity to promote his development into an independent physician-scientist. The mentor, Dr. Paul Simpson, will oversee the project and the career development of the applicant. Dr. Simpson is highly respected in the field of molecular cardiology and internationally-recognized for his contributions to our understanding of cardiac hypertrophy and alpha-1-adrenergic receptor (AR) biology. He also is a trained cardiologist who has guided the successful development of many physician-scientists, hence he is a perfect mentor for this project. UCSF is an ideal setting for the proposed training program, offering expertise in nearly every area of biomedical science, and there is a deep commitment from the institution to the development of the applicant as an independent investigator. The research plan follows naturally from the applicant's recent novel work identifying the tissue distribution of the 3 alpha-1-AR subtypes in the human heart. Abundant data from animal studies, including knockout mouse models created by the mentor, show that the alpha-1 A and alpha-IB subtypes play beneficial roles in the heart and protect against HF. Surprisingly, the function of the human cardiac alpha-1-AR subtypes is unknown, and alpha-1-ARs have never been studied in human heart cells. To address these significant gaps in our knowledge, we propose the following 3 Specific Aims: (I) Maintain and expand the UCSF/San Francisco VA Human Heart Tissue Bank;(M) Identify the alpha-1-AR subtypes in myocytes and fibroblasts from non-failing and failing human hearts, and test their function using isolated cell and whole tissue models;(III) Identify the functional alpha-1-AR subtypes in human coronary smooth muscle and endothelial cells. Collectively these Aims will establish a broader understanding of human cardiac alpha-1-AR biology and the mechanisms of HF. This training program will provide the applicant with valuable skills that will allow him to use human systems to test hypotheses generated in animal models and will serve as the foundation for a successful career in translational HF investigation.

Public Health Relevance

Abundant data from cell and animal studies show that alpha-1-adrenergic receptors (ARs) play beneficial roles in the heart and protect against heart failure (HF), but little is known about these receptors in the human heart. HF is a major clinical problem in the US, and new treatments are badly needed. The proposed work will expand significantly our knowledge of alpha-1-ARs in the human heart and is essential to the long-term aim of the project, which is the development of a novel therapy for HF targeting alpha-1-ARs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL096836-04
Application #
8294717
Study Section
Special Emphasis Panel (ZHL1-CSR-O (M1))
Program Officer
Carlson, Drew E
Project Start
2009-09-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$132,422
Indirect Cost
$9,809
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Reed, Brent N; Street, Sarah E; Jensen, Brian C (2014) Time and technology will tell: the pathophysiologic basis of neurohormonal modulation in heart failure. Heart Fail Clin 10:543-57
Jensen, Brian C; OýýConnell, Timothy D; Simpson, Paul C (2014) Alpha-1-adrenergic receptors in heart failure: the adaptive arm of the cardiac response to chronic catecholamine stimulation. J Cardiovasc Pharmacol 63:291-301
O'Connell, Timothy D; Jensen, Brian C; Baker, Anthony J et al. (2014) Cardiac alpha1-adrenergic receptors: novel aspects of expression, signaling mechanisms, physiologic function, and clinical importance. Pharmacol Rev 66:308-33
Jensen, Brian C; McLeod, Howard L (2013) Pharmacogenomics as a risk mitigation strategy for chemotherapeutic cardiotoxicity. Pharmacogenomics 14:205-13
May, Dalit; Blow, Matthew J; Kaplan, Tommy et al. (2012) Large-scale discovery of enhancers from human heart tissue. Nat Genet 44:89-93
Hong, Ting-Ting; Smyth, James W; Chu, Kevin Y et al. (2012) BIN1 is reduced and Cav1.2 trafficking is impaired in human failing cardiomyocytes. Heart Rhythm 9:812-20
Jensen, Brian C; O'Connell, Timothy D; Simpson, Paul C (2011) Alpha-1-adrenergic receptors: targets for agonist drugs to treat heart failure. J Mol Cell Cardiol 51:518-28
Hong, Ting-Ting; Smyth, James W; Gao, Danchen et al. (2010) BIN1 localizes the L-type calcium channel to cardiac T-tubules. PLoS Biol 8:e1000312
Smyth, James W; Hong, Ting-Ting; Gao, Danchen et al. (2010) Limited forward trafficking of connexin 43 reduces cell-cell coupling in stressed human and mouse myocardium. J Clin Invest 120:266-79
Jensen, Brian C (2010) Skin deep: what can the study of dermal fibroblasts teach us about dilated cardiomyopathy? J Mol Cell Cardiol 48:576-8

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