MOLECULAR & CLINICAL EVALUATION OF LOW HDL SYNDROMES

分子

基本信息

批准号：
6194842
负责人：
MICHAEL MILLER
金额：
$ 35.17万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-08-15 至 2004-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6194842
关键词：
atherosclerosis clinical research family genetics gene expression genetic mapping high density lipoproteins human subject hypolipoproteinemia linkage mapping phenotype

项目摘要

The overall aim of the research proposal is to perform molecular and clinical studies in subjects and affected biologic family members with low levels of high density lipoprotein cholesterol (HDL-C). Whereas an inverse association between HDL-C and coronary artery disease (CAD) is well documented, the genetic basis and potential clinical implications have not been systematically addressed. The specific aims of the proposed research include: 1) Collection and characterization of plasma and DNA from probands with very low HDL-C. Linkage analysis will be performed using highly polymorphic markers within or near HDL- C candidate genes. The hypothesis to be tested is that polymorphic microsatellites segregate with the low HDL-C phenotype. 2) Further genetic characterization of families with evidence of linkage to specific HDL-C candidate genes identified in Specific Aim 1. The hypothesis to be tested is that structural variants in HDL-C candidates are responsible for low HDL-C. 3) Evaluate the physiologic significance of novel genomic variants identified in Specific Aim 2. The hypothesis to be tested is that structural variants will affect expression of the gene product. 4) Examine early atherosclerosis in low HDL-C syndromes. The hypothesis to be tested is that increased carotid intima-medial thickness is prevalent with isolated low HDL-C. Identification of the most extreme forms of this disorder provides a unique opportunity to address these fundamental objectives. Further understanding of the molecular basis of isolated low HDL-C and its potential clinical sequelae (e.g., CAD), may therefore aid in the development of therapeutic strategies to effectively treat this disorder.

该研究计划的总体目标是对高密度脂蛋白胆固醇 (HDL-C) 水平较低的受试者和受影响的生物家族成员进行分子和临床研究。尽管 HDL-C 与冠状动脉疾病 (CAD) 之间的负相关性已得到充分证明，但其遗传基础和潜在的临床意义尚未得到系统解决。拟议研究的具体目标包括： 1) 从 HDL-C 极低的先证者中收集血浆和 DNA 并进行表征。将使用 HDL-C 候选基因内或附近的高度多态性标记进行连锁分析。要测试的假设是多态性微卫星与低 HDL-C 表型分离。 2) 进一步对家族进行遗传表征，并提供与特定目标 1 中确定的特定 HDL-C 候选基因关联的证据。要测试的假设是 HDL-C 候选基因中的结构变异导致低 HDL-C。 3) 评估特定目标 2 中鉴定的新基因组变异的生理意义。要测试的假设是结构变异会影响基因产物的表达。 4) 检查低 HDL-C 综合征中的早期动脉粥样硬化。要检验的假设是颈动脉内膜中层厚度增加普遍存在于孤立性低 HDL-C 中。识别这种疾病的最极端形式为实现这些基本目标提供了独特的机会。因此，进一步了解孤立性低 HDL-C 的分子基础及其潜在的临床后遗症（例如 CAD）可能有助于制定有效治疗这种疾病的治疗策略。