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荷兰莱顿大学医学院 CSC 博士招生 - 基础研究 - 脂质代谢异常和动脉硬化
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A novel lipid transporter as a target for treating dyslipidemia and atherosclerosis Background Cardiovascular disease (CVD), mainly caused by atherosclerosis, is the leading cause of death globally. One of the most important risk factors for atherosclerosis is dyslipidemia, hallmarked by increased plasma levels of (V)LDL-cholesterol (C) and triglycerides, and decreased plasma levels of HDL-C. Lipid-lowering agents including statins improve dyslipidemia and have reduced major cardiovascular events. However, since current lipid-lowering agents only partially improve the mortality and morbidity due to CVD, novel modulators of lipid and lipoprotein metabolism that can be used as targets for treating dyslipidemia are eagerly awaited. In our lab, by performing a genome-wide association analysis (GWAS) in more than 6,000 subjects from a large cohort, we have identified a novel gene encoding a lipid transporter of which genetic variants are strongly associated with plasma lipid levels. Although the biological function of this protein is as yet unknown, our pilot data indicate that it may well play an importantrole in lipid homeostasis via the regulation of intracellular lipid and sterol trafficking. Collectively, we hypothesize that this novel lipid transporte may serve as a promising target for treating dyslipidemia and atherosclerosis. Objectives (1) To investigate the role of this lipid transporter in lipid metabolism (2) To elucidate the mechanisms underlying regulation of cellular lipid homeostasis (3) To investigate the therapeutic application on dyslipidemia and atherosclerosis development in a humanized mouse model Work plan Ad 1. The role of this protein in lipid metabolism will be studied by knock-down using ShRNA and/or CRISPR methods, by overexpression using AAV, both in vitro (specific cell lines) and in vivo (mice). Ad 2. Stable isotope-labeled lipids and lipoproteins will be used to study the role of this protein in cellular cholesterol homeostasis. Potential nuclear signaling that regulates this lipid transporter will be studied in vitro and in vivo. Ad 3. APOE*3-Leiden.CETP mice, our unique humanized mouse model for dyslipidemia and atherosclerosis, will be used for AAV-mediated expression of this protein. Cholesterol removal (biliary and trans-intestinal efflux), and atherosclerosis progression (lesion size, severity and plaque composition) will be determined. Contact details: Dr. Yanan Wang (email: Y.wang@lumc.nl) Prof. dr. Patrick Rensen (email: P.C.N.Rensen@lumc.nl) Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands |
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2楼2017-11-21 16:45:13
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3楼2017-11-21 22:48:41