MOLECULAR & CLINICAL EVALUATION OF LOW HDL SYNDROMES

分子

• 批准号: 6390100
• 负责人: MICHAEL MILLER
• 金额: $ 40.77万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 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/6390100
• 关键词: atherosclerosis; clinical research; family genetics; gene expression; genetic mapping; high density lipoproteins; human subject; hypolipoproteinemia; linkage mapping; phenotype

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.

该研究建议的总体目的是对具有低密度脂蛋白胆固醇（HDL-C）的受试者和影响的生物家庭成员进行分子和临床研究。 虽然HDL-C与冠状动脉疾病（CAD）之间存在逆关联，但遗传基础和潜在的临床意义尚未系统地解决。拟议研究的具体目的包括：1）来自HDL-C非常低的概率的血浆和DNA的收集和表征。 将使用HDL-C候选基因内或附近的高度多态标记进行连锁分析。 要检验的假设是多态微卫星与低HDL-C表型分离。 2）与特定目标中鉴定出的特定HDL-C候选基因有联系的家族的进一步遗传表征1。要检验的假设是HDL-C候选者中的结构变异是低HDL-C的2。 3）评估在特定目标中鉴定出的新型基因组变异的生理意义2。要检验的假设是结构变体将影响基因产物的表达。 4）检查低HDL-C综合征的早期动脉粥样硬化。要测试的假设是，颈动脉内膜厚度增加的情况下是孤立的低HDL-C的普遍性。确定这种疾病最极端形式的形式为解决这些基本目标提供了独特的机会。 因此，进一步了解分离的低HDL-C及其潜在的临床后遗症（例如CAD）的分子基础可能有助于发展治疗策略，以有效治疗该疾病。