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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1-CSR-R (F1))
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Scott, Jane
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Columbia University (N.Y.)
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Ji, Ruiping; Akashi, Hirokazu; Drosatos, Konstantinos et al. (2017) Increased de novo ceramide synthesis and accumulation in failing myocardium. JCI Insight 2:
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
Brunjes, Danielle L; Dunlop, Mark; Wu, Christina et al. (2016) Analysis of Skeletal Muscle Torque Capacity and Circulating Ceramides in Patients with Advanced Heart Failure. J Card Fail 22:347-55
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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
Akat, Kemal Marc; Moore-McGriff, D'Vesharronne; Morozov, Pavel et al. (2014) Comparative RNA-sequencing analysis of myocardial and circulating small RNAs in human heart failure and their utility as biomarkers. Proc Natl Acad Sci U S A 111:11151-6

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