Mechanisms of Hepatic Steatosis Prevention

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DESCRIPTION (provided by applicant): Parental nutrition is life-saving but may produce severe liver injury, resulting in high morbidity and mortality in children. Long-term parenteral nutrition may also produce a slowly progressive liver injury in many adults. Since the development of parenteral nutrition over thirty years ago, there have been few improvements in the prevention and treatment of this liver injury. My primary career objective is to become an independent investigator conducting basic and translational research that advances the development of new therapies in the prevention and treatment of this often-fatal complication of parenteral nutrition. As steps toward this goal, I hope to gain additional training in basic lipid metabolism and the broad field of the biochemistry of matrix metalloproteinases. To guide me in my pursuit of these goals, I have chosen two outstanding recognized mentors and scientists, Dr. Bruce Bistrian and Dr. Marsha Moses. Together with Dr. Judah Folkman, they will also form my advisory committee. I have arranged for courses, conferences and meetings to complement these goals. My proposed research focuses on three aims. First, I intend to determine how matrix metalloproteinase inhibitors prevent steatosis and liver injury in our animal model utilizing in vivo lipid studies and in vitro enzymatic methods to study lipid synthesis, oxidation, and secretion of triglycerides from the liver. Second, I intend to determine the role of specific cytokines in the development of steatosis and its prevention utilizing genetically manipulated mice with and without matrix metalloproteinase inhibitors. Third, I intend to determine the transcription, protein levels, and enzymatic activity of specific metalloproteinases important in the development, prevention, and reversal of steatosis and steatohepatitis. This award would provide me with protected time to pursue these research and training objectives, and greatly facilitate my transition to an independent researcher in the study of this devastating disease