Cardiolipin Biosynthesis and Mitochondrial Energy Production in Pediatric Idiopathic Dilated Cardiomyopathy

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 DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the development of an academic career in the field pediatric heart failure. The principal investigator has MD, Ph.D. training, completed clinical residency training in Pediatrics and Genetics at the Children's Hospital of Philadelphia, and recently completed fellowship training in Pediatric Cardiology at the University of Colorado. During this period of clinical training she has developed an interest in the etiologies of heart failure (HF) in children, and initiated a research program under the primary mentorship of Dr. Brian Stauffer. The proposed research program will be the first to provide a thorough characterization of mitochondrial function and energy metabolism in pediatric idiopathic dilated cardiomyopathy (IDC). The project addresses a critical healthcare disparity in an under-represented and vulnerable population: children who have received little benefit from advances in adult HF treatments. The goal of the work is to impact outcomes of heart failure in children through identification of unique pathophysiologic processes in myocardium of children with IDC, allowing identification of dietary and pharmacologic therapies tailored to pediatric disease. The mentorship team provides a diverse training backgrounds and research expertise in cardiovascular biology. Each member is extramurally funded, a leader in the field of pediatric heart failure and cardiovascular physiology, and committed to their role as research mentors. Preliminary work has demonstrated evidence of changes in mitochondrial content, phospholipid content, and energy capacity in pediatric IDC. This research will focus on further characterization of mitochondrial dysfunction through analysis of stress and biogenesis responses and direct assay of the electron transport chain and mediators of fatty-acid influx for ß-oxidation using human tissue. Features of pediatric HF are recapitulated by treatment of a juvenile mouse with isoproterenol (ISO). This model is proposed as a model to further delineate the mechanisms of altered mitochondrial energy utilization in pediatric HF. The Department of Pediatrics at the University of Colorado Denver provides an ideal setting for training physician-scientists by incorporating expertise and resources from Clinical and Basic Science Departments throughout the University of Colorado System. This environment, with access to a large human heart tissue bank and the principal investigator's mentorship team are ideally suited to ensure the success of a novel area of research upon which a career in translational medicine can be constructed.