Oxidative Stress and Mitochondrial Dysfunction in Chemogenetic Heart Failure

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This K08 Mentored Clinical Scientist Career Development Award describes a five-year research and training program of the principal investigator (PI), Dr. Fotios Spyropoulos, that will enable his transition to independent scientific investigation in the field of oxidative stress-induced cardiac metabolic reprogramming and mitochondrial dysfunction. Premature infants are particularly susceptible to oxidative stress-induced injury and early heart failure is an increasingly recognized complication of preterm birth leading to increased morbidity and mortality. The PI has completed post-graduate training in neonatal-perinatal medicine and his long-term goal is to identify the link between prematurity and heart failure. Thus, the PI’s proposal initially focuses on the characterization of an adult model of chemogenetic heart failure with a plan to apply the skills gained from this award to future investigation of neonatal heart failure models. The PI will use a novel transgenic mouse model (DAAO-TGCar) that enables robust and specific generation of oxidative stress, in the form of hydrogen peroxide (H2O2), in the heart. He aims to delineate the role of oxidative stress in the development of mitochondrial dysfunction and heart failure. He shows novel preliminary data implicating chemogenetic H2O2 mediated inactivation of Sirtuin 3 (Sirt3) in the development of mitochondrial dysfunction. To test this hypothesis the following specific aims are proposed: 1. Characterize the heart failure phenotype of the DAAO-TGCar mouse model, 2. Assess the role of Sirt3 oxidation on cardiac oxidant balance and mitochondrial function, and 3. Determine the mechanisms of H2O2 mediated regulation of cardiomyocyte physiology and energetics. This research has significance, as understanding oxidant stress-induced mitochondrial damage may identify new therapies for the prevention and treatment of this debilitating condition. The PI will perform the proposed work under the co-mentorship of Dr. Michel, expert in oxidant signaling pertaining to cardiovascular biology and heart failure, live-cell imaging, and chemogenetic applications, and Dr. Christou, an expert in vascular biology and cardiovascular physiology. The PI will receive additional guidance from his scholarship oversight committee composed of senior scientists with complementary expertise in cardiac hemodynamics and bioenergetics, mitochondrial biology, and experimental models of heart failure. The training environment and the resources provided by the PI’s institutions, Brigham and Women's Hospital and Harvard Medical School, are ideal for his professional development. The PI is guaranteed >75% protected research time to devote to the proposed K08 program. Mentored research, didactic coursework, and presentations at scientific meetings are all part of a detailed career development and training plan. The PI outlines a timeline for completing the proposed aims, writing scientific manuscripts, and submitting a future R01 application. At the end of this award, the PI will obtain R01 funding and transition to independence by applying the knowledge and concepts gained from this award to future investigations focused on identifying the effects of oxidative stress on the development of the neonatal myocardium.