Lipotoxic Effects of Maternal Diabetes and High Fat Diet on the Developing Heart

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DESCRIPTION (provided by applicant): This project is focused on preventing cardiovascular disease in offspring of diabetic mothers (ODMs). The prevalence of diabetes during pregnancy is escalating, and one third of all infants born to diabetic mothers (IDMs) have cardiac hypertrophy at birth. Despite a healthy lifestyle, IDMs carry a risk of cardiovascular disease into adulthood, proposedly through fuel mediated fetal programming. Current preventative measures focus on glucose control, but normoglycemic women can have affected infants, implicating additional fuel- mediated offenders, including lipids. The relative contribution of excess circulating lipids in developmental programming of cardiac disease is not well recognized, or studied. To better understand this, our research plan utilizes a rodent model of late-gestation diabetes, with a control- or high-fat diet, to simulate cardiac disease experienced by IDMs. Using this model, we mimicked human maternal-placental-fetal interactions, reproducing a triad of maternal hyperglycemia, hyperlipidemia, and fetal hyperinsulinemia. Under these conditions, newborn offspring were affected by cardiac hypertrophy, poor systolic function similar to IDMs. Unexpectedly, we demonstrated that a maternal high-fat diet, not diabetes, markedly increased perinatal mortality in newborns. Offspring that died had enlarged hearts with marked lipid droplet accumulation. Array analysis pointed to altered expression in genes regulating cardiac energy metabolism. These preliminary findings prompted generation of a bioenergetic hypothesis of fuel-mediated developmental programming. Due to its very high energy needs, the heart can rapidly transport, store, and utilize different substrates for energy. Normally, neonatal hearts ar efficient at glycolysis, but adult hearts prefer fatty acid oxidation as a more efficient source of ATP. We propose that exposing the developing heart to excess circulating fuels reprograms substrate metabolism and energy production efficiency, and furthermore, this reprogramming contributes to ongoing cardiac risk throughout life. My lab has validated all proposed methods, collected mounting preliminary data to support our hypothesis, and is now poised to further determine the underlying mechanisms and long-term consequences of maternal diabetes and high-fat diet on the developing heart. We aim to do this through evaluation of structural, functional, histopathologic, cardiovascular risk and bioenergetic markers of cardiac health in our offspring throughout their maturation. My long-term career goal is to understand developmental consequences of maternal or neonatal lipid disturbances, and identify preventative strategies to improve long-term outcomes of high-risk infants. The objective of this application is to utilize th mentored clinical scientist program to establish an independently funded basic science program to study the contribution of excess circulating lipid associated with high-fat intake and diabetic pregnancy in the developmental programming of cardiac disease in offspring. As the candidate, my ability to establish a solid foundation of both basic and clinical research, in addition to year of clinical experience, make me an ideal clinical scientist to take scientific discovery from the bench to the bedside. My scientific foundation has grown rapidly from one translational study evaluating fatty acid levels in human milk samples to the simultaneous implementation of a randomized clinical trial and the development of a basic science laboratory studying lipid-mediated developmental programming. Establishing independently funded research will require that scientific findings reach significance in the field. To accomplish this, a career development plan was established to aid in growth towards fluent independent investigation using a structured, goal-oriented, timeline of presentation, publication and grant submissions. The plan utilizes committed resources, a rich and collaborative institutional environment, and guidance of a trans- disciplinary mentoring team. The unique role of two well-suited co-mentors ensures that day-to-day guidance of both basic science and clinical research is readily available from well established local mentors, Dr. David Pearce and Dr. William Harris. Scientific oversight is enhanced through quarterly advisory committee meetings that include Dr. Norris and Dr. Segar, clinical scientists with proven success in their fields of lipid biochemistry and developmental programming of cardiovascular disease. Dr. Eugene Hoyme, a third advisory committee member, adds leadership and professional development guidance through the advisory committee and monthly Pediatric Mentoring Program meetings. (See Statement by Mentor and Biosketches) The combination of a truly translational candidate, a committed and fostering institution, a customized mentoring team and an innovative research plan with high significance provide the perfect arrangement for a successful clinical scientist in your program. We predict that completion of this project will substantiate the harmful effects of maternal dyslipidemia associated with diabetes and a high-fat diet on the developing fetal heart and promises hope of preventing cardiovascular disease even before it begins.