MOLECULAR STUDIES OF ISOLATED LOW HDL C

这项拟议研究的总体目标是研究分子 分离的低水平高密度脂蛋白胆固醇的基础 (高密度脂蛋白胆固醇)。尽管低高密度脂蛋白和高密度脂蛋白胆固醇之间的联系已经确立 冠心病(CAD)的系统遗传学研究 这一混乱的基础尚未采取行动。探索分子 分离的低高密度脂蛋白胆固醇的基础和相关细胞机制， 受严重影响的受试者和生物家庭成员 在全美范围内被识别。建议的具体目标 研究包括： 1)识别孤立低高密度脂蛋白胆固醇受试者的蛋白质异常 需要检验的假设是，结构上的变化 (载脂蛋白AI)或功能蛋白(LCAT)负责 分离的低高密度脂蛋白胆固醇 2.)发现载脂蛋白AI和LCAT基因的新突变。这个 有待检验的假设是载脂蛋白AI基因的突变会改变很高 成纤维细胞的亲和力结合和胆固醇流出 LCAT基因的突变改变了酶活性的表达。 3.)确定新的突变或特定的遗传标记 隔离低高密度脂蛋白胆固醇和/或过早的冠心病。需要检验的假设 多态的DNA微卫星区域是否在 孤立的低高密度脂蛋白胆固醇家系最具代表性的主题集合 这种疾病的极端形式提供了理想的人群来解决 这个根本性的问题。这些系统的研究应该阐明 孤立低高密度脂蛋白胆固醇作为冠心病危险因素的意义 未来发展治疗策略的先决条件 对这种混乱的管理。

The overall aim of the proposed research is to investigate the molecular basis of an isolated low level of high density lipoprotein cholesterol (HDL-C). Despite the well-established association between low HDL-C and coronary artery disease (CAD), a systematic investigation of the genetic basis for this disorder has not been undertaken. To explore the molecular basis and associated cellular mechanisms underlying isolated low HDL-C, severely affected subjects and biologic family members have been identified throughout the United States. The specific aims of the proposed research include: 1.) Identify protein abnormalities in subjects with isolated low HDL-C. The hypothesis to be tested is that alterations in structural (apolipoprotein AI) or functional (LCAT) proteins are responsible for isolated low HDL-C. 2.) Identify novel mutations in the apolipoprotein AI and LCAT gene. The hypothesis to be tested is that mutations in the apo AI gene alters high affinity binding and cholesterol efflux in cultured fibroblasts and mutations in the LCAT gene alter expression of enzymatic activity. 3.) Determine whether novel mutations or specific genetic markers segregate with low HDL-C and/or premature CAD. The hypothesis to be tested is whether polymorphic DNA microsatellite regions are informative in families with isolated low HDL-C. The collection of subjects with the most extreme forms of this disorder provides the ideal population to address this fundamental question. These systematic studies should elucidate the significance of isolated low HDL-C as a risk factor for CAD and serve as prerequisite for future development of therapeutic strategies in the management of this disorder.