This application for a Mentored Clinical Scientist Development Award proposes to train a physician specializing in pediatric endocrinology to become an independent investigator in the molecular, cellular, and pathologic mechanisms of lipoprotein disorders. Training will include didactic course work, seminars, journal clubs, oral presentations, a research advisory committee, and research in which the respective roles of the catalytic and ligand functions of hepatic lipase, a crucial component of lipoprotein metabolism, will be studied in transgenic mice. For the past three years the applicant has developed and characterized functional mutants of hepatic lipase (HL) in vitro. To extend these in vitro results, the applicant has created transgenic mice expressing these mutant HLs. The enzyme HL is a crucial component in the metabolism of atherogenic lipoprotein remnants and antiatherogenic high density lipoproteins. However, its role in atherogenesis is controversial. In vitro HL functions both as a catalyst and ligand. The overall objective of this proposal is to establish the respective contributions of the catalytic and ligand functions of HL to lipoprotein metabolism in vivo.
Specific Aim 1 seeks to determine the physiologic significance of the catalytic function by studying transgenic mice expressing a catalytically inactive HL.
Specific Aim 2 seeks to determine the physiologic significance of HL as a direct ligand in mediating uptake of specific lipoproteins by studying transgenic mice expressing HL mutants with defective ligand binding.
These aims will be accomplished by comparing the plasma lipoprotein profiles, and the plasma turnover and liver uptake of radiolabeled lipoproteins.
Specific Aim 3 is designed to determine the impact of HL and its functional mutants on atherosclerosis development. The studies will be performed at the Gladstone Institute of Cardiovascular Disease, an internationally renowned research institution respected for its high quality scientific publications in the lipoprotein metabolism and cardiovascular disease research fields. The J. David Gladstone Institute has state-of-the-art facilities and equipment including a full barrier transgenic animal facility.
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