PATHOBIOLOGICAL DETERMINANTS OF ATHEROSCLEROSIS IN YOUTH

青年动脉粥样硬化的病理学决定因素

• 批准号: 3356881
• 负责人: JAMES E. HIXSON
• 金额: $ 13.89万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-01 至 1993-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3356881
• 关键词: adolescence (12-20); apolipoproteins; atherosclerosis; blood lipid; blood pressure; cholesterol; diabetes mellitus; disease /disorder proneness /risk; genetic markers; genotype; human genetic material tag; human tissue; low density lipoprotein; molecular pathology; nucleic acid probes; obesity; postmortem; southern blotting; tobacco abuse; young adult human (21-34)

The overall goal of the proposed research is to identify specific genes that mediate the pathogenesis of arterial lesions. The proposed research is part of a multicenter study to examine arterial lesions in 3000 young persons (15-34 years), and to identify risk factors that are associated with extent and nature of atherosclerotic lesions. This proposal is in response to recommendations of the review committee for phase I of the multicenter study to include genetic analyses (using restriction fragment length polymorphisms, RFLPs) that will detect associations between specific genes and atherogenesis. The long- term objectives of the multi-center study are: (1) to define more precisely the developmental processes by which arterial lesions characteristic of late childhood (fatty streaks) progress to form advanced lesions (fibrous plaques) associated with atherosclerosis in adulthood, and (2) to relate selected risk factors (serum cholesterol) and lipoprotein concentrations, cigarette smoking, blood pressure, diabetes, and obesity) to characteristics of atherosclerotic lesions in young persons. The aims of this proposed research relate to the second objective of the multi-center study and include: (1) determination of genotypes for each subject with respect to RFLPs in apolipoprotein and the LDL receptor genes (Southern blot analyses of DNA from liver samples sent from each collection center), (2) typing of subjects for apo E isoform genotypes using oligonucleotide probes, and (3) examination of the effects of RFLP genotypes on extent and characteristics of arterial lesions in young people. Detection of an associated RFLP not only provides evidence for genetic mediation of the pathogenesis of arterial lesions, but identifies which gene(s) is responsible for the underlying molecular processes of atherosclerosis. To maximize the probability of detecting RFLPs associated with pathogenesis of arterial lesions, specific RFLPS have been selected from published reports from other studies of human subjects. Most of these RFLPs have previously been associated with heart disease or altered levels of serum lipids and lipoproteins. This proposal presents a unique and important extension to genetic studies of heart disease, and will be the first direct examination of the effects of specific genes on the early stages of atherosclerotic lesions in young persons.

拟议研究的总体目标是确定特定的 介导动脉病变发病机理的基因。 这 拟议的研究是一项多中心研究的一部分 3000名年轻人（15-34岁）的动脉病变， 确定与范围和性质相关的风险因素 动脉粥样硬化病变。 该建议是对 第一阶段审查委员会的建议 多中心研究以包括遗传分析（使用限制 片段长度多态性，rflps）将检测到 特定基因与动脉粥样硬化之间的关联。 长期 多中心研究的术语目标是：（1）定义更多 正是动脉病变的发育过程 童年晚期（脂肪条纹）的特征进步 与动脉粥样硬化有关的晚期病变（纤维斑块） 成年和（2）关联选定的危险因素（血清 胆固醇）和脂蛋白浓度，吸烟， 血压，糖尿病和肥胖症） 年轻人的动脉粥样硬化病变。 这项拟议研究的目的与第二个目标有关 多中心研究，包括：（1）确定 每个受试者关于RFLP的基因型 载脂蛋白和LDL受体基因（Southern印迹分析 从每个收集中心发送的肝样品的DNA），（2） 使用使用APO E同工型基因型的受试者使用 寡核苷酸探针和（3）检查 RFLP基因型关于动脉病变的程度和特征 在年轻人中。 检测相关的RFLP不仅 提供证据证明遗传介导的发病机理 动脉病变，但确定了基因的原因 动脉粥样硬化的基本分子过程。 最大化 检测与发病机理相关的RFLP的概率 在动脉病变中，已选择了特定的RFLP 发表了其他关于人类受试者的研究的报告。 大多数 这些RFLP以前与心脏病有关 或血清脂质和脂蛋白水平改变。 这个建议 提出了对遗传研究的独特而重要的扩展 心脏病，将是首次直接检查 特定基因对动脉粥样硬化的早期阶段的影响 年轻人的病变。