Anti-inflammatory properties of high-density lipoprotein

描述(由申请人提供)： 人们普遍认为，高密度脂蛋白(高密度脂蛋白)通过清除动脉细胞中多余的胆固醇来预防动脉粥样硬化。除了高密度脂蛋白在胆固醇转运和清除中的作用外，越来越多的证据支持它在体内作为一种重要的细胞炎症和脂质氧化抑制因子的功能。此外，炎症被认为可以将高密度脂蛋白转化为一种功能失调的形式，从而失去这些心脏保护作用，甚至可能是促炎作用。导致高密度脂蛋白致炎的潜在因素仍然知之甚少。两条重要的途径可能涉及氧化损伤和高密度脂蛋白中促氧化蛋白和抗氧化蛋白相对平衡的变化。 该提案概述了一个高度结构化的职业发展计划，该计划将促进申请者向完全独立的调查员过渡。该提案的主要组成部分是大量接触基础科学研究，这些研究将检验这样一种假设，即蛋白质的氧化和变化削弱了高密度脂蛋白的抗炎和心脏保护作用。申请者将在获奖的头两年接受指导。这段时间的培训将建立在他在质谱学方面的强大背景之上，并将他的专业知识扩展到模型系统研究、计算生物学和高胆固醇血症的动物模型。申请者还将启动翻译研究，使用蛋白质组学方法来定义高密度脂蛋白的蛋白质货物。在获奖的最后三年，申请者将开发一项独立的研究计划，以了解高密度脂蛋白在血管壁生物学中的作用，重点是炎症和动脉粥样硬化的小鼠模型。 长期目标是让申请者成为一名完全独立的生物医学研究员，在NIH资助的学术医学中心担任终身教职。

DESCRIPTION (provided by applicant): It is widely believed that high-density lipoprotein (HDL) protects against atherosclerosis by removing excess cholesterol from arterial cells. In addition to HDL's role in cholesterol transport and removal, increasing evidences support its functions as an important inhibitor of cellular inflammation and lipid oxidation in vivo. Moreover, inflammation has been proposed to convert HDL to a dysfunctional form that loses these cardio protective effects and may even be pro-inflammatory. The underlying factors that render HDL pro-inflammatory remain poorly understood. Two important pathways may involve oxidative damage and changes in the relative balance of pro- and antioxidant proteins in HDL. This proposal outlines a highly structured career development plan that will promote the transition of the applicant to a fully independent investigator. The major component of the proposal is intense exposure to basic science studies that will test the hypothesis that oxidation and changes in the protein cargo impair the anti inflammatory and cardio protective effects of HDL. The applicant will be mentored during the first two years of the award. This period of training will build upon his strong background in mass spectrometry and extend his expertise to model system studies, computational biology, and animal models of hypercholesterolemia. The applicant will also initiate translational studies that will use a proteomics approach to define the protein cargo of HDL. In the last three years of the award, the applicant will develop an independent research program centered on understanding the role of HDL in vascular wall biology, with an emphasis on murine models of inflammation and atherosclerosis. The long term goal is to establish the applicant as a fully independent biomedical investigator in an NIH-funded tenure-track position at an academic medical center.