CELLULAR DISORDERS IN FAMILIAL HDL DEFICIENCIES

人群研究表明，血浆HDL 水平和冠心病的风险，这表明HDL可以保护 对抗动脉粥样硬化- 这种保护可能与能力有关 刺激外周细胞胆固醇清除， 特别是动脉壁的那些。载脂蛋白A-I，主要的蛋白质， 血浆HDL，促进胆固醇和磷脂流出，并刺激 从培养细胞清除胆固醇酯。我们发现这些apo A-I介导的脂质转运过程几乎不存在， 来自两名丹吉尔病（一种遗传性疾病）患者的成纤维细胞 其特征是血浆HDL水平极低，大量沉积 组织中胆固醇酯的含量，以及心血管疾病的高患病率 疾病我们还发现apoA-I与细胞表面的相互作用 丹吉尔成纤维细胞的结合位点异常，这可能是基础 脂质转运受损的原因载脂蛋白A-I未能获得细胞 胆固醇和磷脂可以解释快速的 新生HDL颗粒与Tangier病低血浆HDL水平 家族性HDL缺乏症（FHD）我们建议确定 不同成纤维细胞系中脂质转运障碍的患病率 从丹吉尔病和FHD患者，并评估参与 相同或不同的基因型，使用互补分析。我们 也将表征细胞过程中的缺陷， 载脂蛋白介导的脂质从丹吉尔成纤维细胞的去除 细胞表面载脂蛋白结合位点的性质比较 正常和Tangier成纤维细胞，并通过测定载脂蛋白- 介导的信号传导事件在Tangier细胞中是异常的。最后，我们将 鉴定在正常人和正常人之间差异表达的基因产物， 二维凝胶电泳和mRNA差异显示技术检测Tangier细胞。 这些研究将产生关于细胞的重要信息， 丹吉尔病和其他FHD的表型和基因型， 将提供深入了解HDL的分子特性 细胞中载脂蛋白介导的胆固醇排泄途径。一 对这一通路的更深入了解可能会提示治疗方法 用于纠正与以下疾病相关的获得性和遗传性细胞疾病： 血浆高密度脂蛋白水平低和心脏病风险增加。

Population studies have shown an inverse correlation between plasma HDL levels and risk for coronary heart disease, suggesting that HDL protects against atherosclerosis. -This protection may be related to the ability of HDL to stimulate clearance of cholesterol from peripheral cells, particularly those of the artery wall. Apo A-I, the major protein of plasma HDL, promotes cholesterol and phospholipid efflux and stimulates cholesteryl ester clearance from cultured cells. We found that these apo A-I-mediated lipid transport processes are virtually absent in fibroblasts from two patients with Tangier disease, a genetic disorder characterized by extremely low plasma levels of HDL, massive deposition of cholesterol esters in tissues, and a high prevalence of cardiovascular disease. We also found that the interaction of apo A-I with cell-surface binding sites is abnormal for Tangier fibroblasts, which may be the basis for the impaired lipid transport. Failure of apo A-I to acquire cellular cholesterol and phospholipids may account for the rapid catabolism of nascent HDL particles and the low plasma HDL levels in Tangier disease and other familial HDL deficiencies (FHDs). We propose to determine the prevalence of lipid transport disorders among different fibroblast lines from patients with Tangier disease and FHDs and to assess the involvement of the same or different genotypes using complementation analysis. We will also characterize the cellular processes defective in apolipoprotein-mediated removal of lipids from Tangier fibroblasts by comparing properties of cell-surface apolipoprotein binding sites between normal and Tangier fibroblasts and by determining if apolipoprotein- mediated signalling events are abnormal in Tangier cells. Lastly, we will identify gene products differentially expressed between normal and Tangier cells by 2-D gel electrophoresis and mRNA differential display. These studies will generate important information about the cellular phenotypes and genotypes that underlie Tangier disease and other FHDs and will provide insight into the molecular properties of the HDL apolipoprotein-mediated cholesterol excretory pathways in cells. A greater understanding of this pathway may suggest therapeutic approaches for correcting acquired and genetic cellular disorders associated with low plasma HDL levels and increased risk for heart disease.