Metabolic regulation in growth factor-dependent cells

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DESCRIPTION (provided by applicant): This proposal outlines a comprehensive plan for the PI to develop an academic career in Biochemical Genetics. The candidate, an Instructor in Pediatrics at The Children's Hospital of Philadelphia (CHOP), receives basic science research mentoring from Craig Thompson, MD at the University of Pennsylvania, and clinical mentoring from Marc Yudkoff, MD of CHOP'S Division of Child Development, Rehabilitation Medicine and Metabolic Disease. Pediatric mitochondrial diseases are untreatable genetic disorders that disrupt metabolism of lipids and other substances. They impair many tissues, including the bone marrow, where failure of cell proliferation results in increased susceptibility to infection. Because cells in the bone marrow depend on growth factor stimulation to direct their metabolism, we hypothesize that mitochondrial diseases prevent growth factors from eliciting metabolic responses needed to support the cell proliferation characteristic of immune responses. We propose to study how growth factors stimulate synthesis of fatty acids and lipids, because they must be produced in abundance in order for cells to proliferate. Our long-term goal is to understand why genetic defects in mitochondrial metabolism impair lipid synthesis in growth factor - dependent cells, and to use this information to improve the health of children with such diseases. In our first aim, we study how growth factor stimulation of the kinase Akt directs fatty acid synthesis. In our second aim, we study the mechanism and importance of growth factor suppression of fatty acid degradation. In our third aim, we focus on defects in the mitochondrial electron transport chain (ETC) that impair lipid synthesis. We will establish models of ETC dysfunction and use them to test the hypothesis that activation of the kinase AMPK orchestrates abnormalities in lipid metabolism seen in ETC diseases. Mitochondrial diseases continue to be a significant source of mental retardation, morbidity and mortality in children. Diagnosis and treatment of these disorders continues to be inadequate, in part because of an incomplete understanding of their pathophysiology. The studies proposed here will provide a foundation to understand connections between growth factor signaling, lipid biology and mitochondrial metabolism, and could suggest new therapeutic avenues to improve growth and immune function in these children.