This proposal details a comprehensive 5-year training program for my career development in academic Cardiovascular Medicine. After completion of clinical training in Cardiovascular Medicine at Columbia University Medical Center, I plan to embark on a mentored research program to provide additional scientific training necessary for an independent career in biomedical research. I will gain in-depth experience in cellular biology, genetics, molecular biochemistry, metabolism, and in vivo physiology as applied to derangements of metabolism and exercise tolerance in patients with chronic heart failure. Drs. Donna Mancini and Ira Goldberg will mentor my scientific and career development. Dr. Mancini is an internationally recognized leader in the fields of heart failure and transplant, exercise physiology and metabolism in cardiovascular diseases, and has a proven track record for successful career mentorship in academic medicine and the basic sciences. Dr. Ira Goldberg is an expert in vascular and myocardial metabolism and insulin signaling in diabetes mellitus. In addition, an advisory committee of established basic cardiovascular and clinician scientists (Drs. Andrew Marks, Ira Tabas, Ulrich Jorde, Yoshifuma Naka, Zhezhen Jin) and administrators (Dr. Jamie Rubin) will provide scientific and career advice. The central hypothesis of this application is that common gene expression patterns and metabolic derangements determine structural and functional changes in skeletal muscle and myocardium of patients with HF and that those changes are reversible after hemodynamic improvement through ventricular assist device placement. Previously, I have shown that local anabolic function in skeletal muscle is impaired in heart failure and that progressive muscle wasting develops through activation of muscle proteolysis.
My aims are: 1) To characterize the role of the ubiquitin-proteasome-system in skeletal muscle atrophy in patients with heart failure;2) To analyze metabolic changes in atrophying skeletal muscle of patients with heart failure;3) To assess the impact of hemodynamic improvement after ventricular assist device placement on myocardial and skeletal muscle metabolism and proteolysis in patients with heart failure.

Public Health Relevance

Heart failure is an expanding worldwide epidemic that already affects more than 5 million people in the US. Exercise intolerance and muscle wasting result from impaired peripheral metabolism and are predictors of mortality in heart failure.
This research aims to understand the fundamental interactions of skeletal muscle and myocardial metabolism and function with the ultimate goal of discovering new therapies to prevent or treat the functional decline in patients with heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL095742-05
Application #
8450259
Study Section
Special Emphasis Panel (ZHL1-CSR-R (F1))
Program Officer
Scott, Jane
Project Start
2009-07-15
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$135,351
Indirect Cost
$10,026
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Coromilas, Ellie; Que-Xu, Em-Claire; Moore, D'Vesharronne et al. (2016) Dynamics and prognostic role of galectin-3 in patients with advanced heart failure, during left ventricular assist device support and following heart transplantation. BMC Cardiovasc Disord 16:138
Martin, Spencer T; Kato, Tomoko S; Farr, Maryjane et al. (2015) Similar survival in patients following heart transplantation receiving induction therapy using daclizumab vs. basiliximab. Circ J 79:368-74
Farr, Maryjane; Mitchell, James; Lippel, Matthew et al. (2015) Combination of liver biopsy with MELD-XI scores for post-transplant outcome prediction in patients with advanced heart failure and suspected liver dysfunction. J Heart Lung Transplant 34:873-82
Khawaja, Tuba; Greer, Christine; Thadani, Samir R et al. (2015) Increased regional epicardial fat volume associated with reversible myocardial ischemia in patients with suspected coronary artery disease. J Nucl Cardiol 22:325-33
Givens, Raymond C; Dardas, Todd; Clerkin, Kevin J et al. (2015) Outcomes of Multiple Listing for Adult Heart Transplantation in the United States: Analysis of OPTN Data From 2000 to 2013. JACC Heart Fail 3:933-41
Wu, Christina; Kato, Tomoko S; Ji, Ruiping et al. (2015) Supplementation of l-Alanyl-l-Glutamine and Fish Oil Improves Body Composition and Quality of Life in Patients With Chronic Heart Failure. Circ Heart Fail 8:1077-87
Chung, Christine J; Wu, Christina; Jones, Meaghan et al. (2014) Reduced handgrip strength as a marker of frailty predicts clinical outcomes in patients with heart failure undergoing ventricular assist device placement. J Card Fail 20:310-5
Forman, Daniel E; Daniels, Karla M; Cahalin, Lawrence P et al. (2014) Analysis of skeletal muscle gene expression patterns and the impact of functional capacity in patients with systolic heart failure. J Card Fail 20:422-30
Prosdocimo, Domenick A; Anand, Priti; Liao, Xudong et al. (2014) Kruppel-like factor 15 is a critical regulator of cardiac lipid metabolism. J Biol Chem 289:5914-24
Schulze, P Christian; Kitada, Shuichi; Clerkin, Kevin et al. (2014) Regional differences in recipient waitlist time and pre- and post-transplant mortality after the 2006 United Network for Organ Sharing policy changes in the donor heart allocation algorithm. JACC Heart Fail 2:166-77

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