The primary goal described in this 5 year training program is the development of a career in academic Pediatric Cardiology. The principal investigator has completed clinical training w/ith two additional years focused on laboratory- based research. This proposal will extend the principal investigator's scientific skills through investigation into the role of metabolic substrate utilization changes in the development and maintenance of compensated cardiac hypertrophy. This plan includes the sponsor, Dr. Michael Portman, an expert on cardiac metabolism. Dr. David Hockenbery, co- mentor and consultant, will assist the project with his extensive knowledge on bioenergenic regulation of cell growth and division. Co-mentor Dr. Charles Murry (LJW) is an expert on cardiomyocyte development and regeneration will provide mentorship in evaluation of hypertrophy. A training plan is presenting including specific coursework, conferences and the formation of an Advisory Committee lo guide his development into a successful independent investigator. C-Myc (Myc) regulates hypertrophy and maintains cardiac function. However, the mechanisms are mostly unknown. The oncology literature identifies specific Myc gene networks including carbohydrate metabolism. Due to known links between metabolism and hypertrophy, we will investigate the metabolic network. We hypothesize that: Myc signals a metabolic shift towards carbohydrate utilization and that this shift mediates the development and maintenance of compensated hypertrophy.
Our aims i nclude: 1) Determine if a metabolic shift towards increased carbohydrate utilization temporally precedes the development of hypertrophy in Myc-induced mice, 2)Determine if inhibiting the Myc- induced substrate shift impairs the development and/or maintenance of compensated hypertrophy in these mice, 3)Determine whether Myc is a major mediator of increased myocardial carbohydrate metabolism in the response to pressure overload, 4) Determine if Myc induction in long-term aortic banded mice can preserve compensated hypertrophy through changes in cardiac substrate utilization. Children's Hospital has a strong commitment to basic science research and the development of physician-scientists. The University of Washington has a vibrant cardiovascular research community which can provide technical expertise as needed. The combined resources of these institutions will provide ample opportunity for the principal investigator to successfully develop into an academic pediatric cardiologist.

Public Health Relevance

Heart failure has an annual mortality rate of around 10% in adults, therefore, researchers are constantly trying to identify new therapies to improve patient outcomes. The protooncogene Myc regulates compensated hypertrophy. A mechanistic understanding of the beneficial aspects of Myc-induced hypertrophy offers the potential for developing novel therapies for heart failure in adults and children.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1-CSR-O (M1))
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Carlson, Drew E
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Seattle Children's Hospital
United States
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Ledee, Dolena; Smith, Lincoln; Bruce, Margaret et al. (2015) c-Myc Alters Substrate Utilization and O-GlcNAc Protein Posttranslational Modifications without Altering Cardiac Function during Early Aortic Constriction. PLoS One 10:e0135262
Olson, Aaron K; Ledee, Dolena; Iwamoto, Kate et al. (2013) C-Myc induced compensated cardiac hypertrophy increases free fatty acid utilization for the citric acid cycle. J Mol Cell Cardiol 55:156-64
Priddy, Colleen M O'Kelly; Kajimoto, Masaki; Ledee, Dolena R et al. (2013) Myocardial oxidative metabolism and protein synthesis during mechanical circulatory support by extracorporeal membrane oxygenation. Am J Physiol Heart Circ Physiol 304:H406-14
Ledee, Dolena; Portman, Michael A; Kajimoto, Masaki et al. (2013) Thyroid hormone reverses aging-induced myocardial fatty acid oxidation defects and improves the response to acutely increased afterload. PLoS One 8:e65532
Olson, Aaron K; Bouchard, Bertrand; Ning, Xue-Han et al. (2012) Triiodothyronine increases myocardial function and pyruvate entry into the citric acid cycle after reperfusion in a model of infant cardiopulmonary bypass. Am J Physiol Heart Circ Physiol 302:H1086-93