DEFICIENCY OF THE HDL RECEPTOR, SR-BI, IN HUMANS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。大多数观察性研究支持这样的概念，即理想的高密度脂蛋白胆固醇水平与心血管疾病呈负相关，即使在低密度脂蛋白胆固醇升高的情况下也是如此。尽管如此，一部分高密度脂蛋白和低密度脂蛋白水平升高的患者患心血管疾病的风险增加。对一个缺乏高密度脂蛋白清道夫受体SR-B1的家系和基因敲除小鼠的研究，概括了这种血脂异常(高密度脂蛋白和低密度脂蛋白)综合征与心血管疾病的增加。这些研究人员假设，一部分高密度脂蛋白和低密度脂蛋白升高的个体将是SR-B1缺陷。将检验三个具体目标：1)表征高密度脂蛋白和低密度脂蛋白胆固醇升高受试者的脂蛋白组成和高密度脂蛋白胆固醇酯的部分清除；2)评估来自研究对象的巨噬细胞中SR-B1的功能和表达；3)确定研究对象中SR-B1基因的变异。这项工作的首要目标是为SR-B1在人类血脂异常和动脉粥样硬化中的作用提供新的见解，并挑战“理想的”高密度脂蛋白胆固醇水平总是具有心脏保护作用的概念。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Most observational studies support the concept that the desirable levels of HDL cholesterol are inversely correlated to cardiovascular disease even in the presence of elevated LDL cholesterol. Nonetheless, a subset of patients with desirable HDL and elevated LDL levels are at increase risk for CVD. Studies in one family and knockout mice deficient in the HDL scavenger receptor, SR-B1, recapitulate this dyslipidemic (elevated HDL and LDL) syndrome with increased CVD. These investigators hypothesize that a subset of individuals with elevated HDL and LDL will be SR-B1 deficient. Three specific aims will be examined 1) characterize the lipoprotein composition and fractional clearance of HDL-cholesterol ester in subjects with elevated HDL and LDL cholesterol; 2)asses SR-B1 function and expression in macrophages derived from study subjects 3)identify variant within the SR-B1 gene in study subjects. The overarching goal of this work is to provide new insights into the role of SR-B1 in human dyslipidemia and atherosclerosis and challenge the concept that "desirable" HDL cholesterol levels are always cardioprotective.