MOLECULAR STUDIES OF ISOLATED LOW HDL C

拟议研究的总体目标是研究分子 高密度脂蛋白胆固醇水平低的基础 （HDL-C）。尽管低HDL-C和高脂血症之间的关系已经得到了很好的证实， 冠状动脉疾病（CAD），一个系统的调查，遗传 这种混乱的基础还没有得到解决。为了探索分子 孤立性低HDL-C的基础和相关细胞机制， 严重受影响的受试者和生物学家族成员 在美国各地都有发现。建议的具体目标 研究包括： 1.）确定孤立性低HDL-C受试者的蛋白质异常。 有待检验的假设是， （载脂蛋白AI）或功能性（LCAT）蛋白负责 孤立性低HDL-C。 2.）的情况。识别载脂蛋白AI和LCAT基因中的新突变。的 有待检验的假设是，载脂蛋白AI基因的突变改变了载脂蛋白AI基因的高表达， 培养的成纤维细胞中的亲和结合和胆固醇流出， LCAT基因的突变改变了酶活性的表达。 3.）第三章确定是否有新的突变或特定的遗传标记 与低HDL-C和/或过早CAD分离。待测试的假设 多态性DNA微卫星区域是否能提供 孤立性低HDL-C家族。最受欢迎的主题集合 这种疾病的极端形式提供了理想的人口来解决 这个基本问题。 这些系统的研究应阐明 孤立性低HDL-C作为CAD危险因素的意义 治疗策略的未来发展的先决条件 管理这种混乱。

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.