The HDL receptor, scavenger receptor Class B type I (Sr-BI), mediates cellular delivery of HDL cholesterol by selective lipid uptake, a mechanism distinct from classic receptor-mediated endocytosis. In addition, SR-BI can bind LDL and VLDL and can mediate both cellular uptake of non-lipoprotein cholesterol and stimulate cellular cholesterol efflux.. In vivo studies with mice, including hepatic over-expression of SR-BI and analysis of SR-BI homozygous null mutants (SR-BI KO), have shown that SR-BI plays a key role 1) in determining the levels of plasma HDL and biliary cholesterol and HDL structure, 2) in mediating the regulated delivery of HDL-cholesterol to steroidogenic tissues and the liver, and 3) in protecting against atherosclerosis. On a chow-fed apoE KO genetic background (standard murine model of spontaneous atherosclerosis), homozygous SR-BI KO causes dramatically accelerated atherosclerosis.. In addition, these mice ('dKO') express multiple cardiac conduction defects. They die between 5-7 weeks of age. The unique properties of the dKO mice raise the possibility that they may serve as a powerful model for some forms of human CHD, providing new mechanistic insight and a platform for preliminary model for some forms of human CHD, providing new mechanistic insights and a platform for preliminary analysis for new treatment of prevention strategies. The twin goals of this Project are I) to characterize the mechanisms underlying early onset CHD and death in dKO mice, and to assess the validity of the dKO mouse as a model for human CHD and death in dKO mice, and to assess the validity of the dKO mouse as a model for human CHD, and II) to identify and characterize-using somatic cell and molecular genetics-the cellular machinery and mechanisms which underlie SR-BI's profound effects on the murine cardiovascular system. A wide array of molecular, cellular, physiologic, imaging, genetic, genomic and pharmacologic approaches will be used in close conjunction with the other Projects and Core Facilities. For example, 1) we will evaluate the influences on dKO CHD of virus-mediated cardiac-specific transgene expression, 2) we will use transcription profile 'fingerprinting' to assess disease progression and the consequences of potential therapeutic interventions, and 3) we will employ recently developed positive/negative mutant selections and retrovirus library-based gene cloning methods to identify gene products and functions essential for SR-BI activity at the cellular level. The proposed work should help elucidate key biological mechanisms underlying cardiovascular function and pathophysiology.
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