IMMUNOCHEMICAL STRUCTURE/FUNCTION OF APOLIPOPROTEIN A-I

载脂蛋白 A-I 的免疫化学结构/功能

• 批准号: 3362582
• 负责人: Linda K Curtiss
• 金额: $ 23.41万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 1992-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3362582
• 关键词: apolipoproteins; chemical fingerprinting; cholesterol; cholesterol esters; enzyme induction /repression; epitope mapping; fibrinolysis; high density lipoproteins; human subject; immunochemistry; laboratory mouse; laboratory rabbit; laboratory rat; macrophage; monoclonal antibody; phosphatidylcholine sterol acyltransferase; protein structure function; steroid biosynthesis; synthetic peptide

Apolipoprotein (apo) A-I is the major apoprotein of plasma high density lipoproteins (HDL). Plasma lipoproteins play pivotal roles in cholesterol metabolism and are important factors for identifying those people at risk for atherosclerosis, stroke and cardiovascular disease. Individuals with high levels of circulating HDL are at lower risk for the complications of atherosclerosis. Numerous functions of apo A-I have been identified that contribute to its beneficial properties. These include the capacity of apo A-I to: 1) activate the enzyme that esterifies cholesterol in plasma, lecithin: cholesterol acyl transferase (LCAT), b) mediate cholesterol delivery to steroidogenic tissues, c) facilitate cholesterol egress from certain nonhepatic peripheral cells such as the cholesteryl ester loaded macrophage (e.g., the foam cells of the atherosclerotic lesion), and d) enhance fibrinolysis. Thus, apo A-I plays an important role in vascular biology and cholesterol metabolism. The primary structure of apo A-I is known, however, specific regions of apo A-I that are responsible for carrying out these functions are largely unknown. Using an immunochemical approach, the relationship between apoprotein structure and function will be explored. Four functions will be studied including LCAT activation, cholesterol delivery to steroidogenic cells, cholesterol unloading from macrophages, and the enhancement of fibrinolysis. An existing panel of apo A-I-specific monoclonal antibodies, which are directed towards unique regions on apo A-I, will be screened for their ability to block each of these apo A-I functions. When antibodies are found that interfere with a particular function, the fragments that represent the functionally important regions of apo A-I will be tested for their ability to either mimic or block apo A-I function. These studies will verify the hypothesis that specific structural regions on apo A-I can be identified that are responsible for each of its many functions. Furthermore, the successful completion of these studies will begin to provide detailed information regarding the specificity mechanism and physiologic importance of the activation of LCAT, cellular interactions, and the enhancement of fibrinolysis by apo A-I.

载脂蛋白（APO）A-I是血浆高密度的主要载脂蛋白 脂蛋白（HDL）。 血浆脂蛋白在胆固醇中起关键作用 代谢，是识别那些处于危险的人的重要因素 用于动脉粥样硬化，中风和心血管疾病。 有个人 高水平的循环HDL的并发症的风险较低 动脉粥样硬化。 已经确定了apo a-i的许多功能 有助于其有益特性。 这些包括Apo的容量 A-1至：1）激活酯化胆固醇血浆中的酶， 卵磷脂：胆固醇酰基转移酶（LCAT），b）介导胆固醇 递送到类固醇组织，c）促进胆固醇的出口 某些非肝脏外围细胞，例如胆固醇酯 巨噬细胞（例如，动脉粥样硬化病变的泡沫细胞）和D） 增强纤维蛋白溶解。 因此，Apo A-I在血管中起重要作用 生物学和胆固醇代谢。 apo a-i的主要结构是 然而，已知apo a-i的特定区域负责 执行这些功能在很大程度上是未知的。 使用免疫化学 方法，载蛋白结构与功能之间的关系将 被探索。 将研究四个功能，包括LCAT激活， 胆固醇递送到类固醇细胞，从胆固醇中卸载 巨噬细胞，以及纤维蛋白溶解的增强。 现有的APO面板 A-I特异性单克隆抗体，针对独特 APO A-I的区域将被筛选，以阻止其每一个 这些apo a-i功能。 当发现抗体会干扰 特定功能，代表功能的片段 APO A-I的重要区域将被测试 模拟或块APO A-I函数。 这些研究将验证假设 可以确定Apo A-I上的特定结构区域 负责其众多功能。 此外，成功 这些研究的完成将开始提供详细的信息 关于特异性机制和生理重要性 LCAT的激活，细胞相互作用和增强 Apo A-I的纤维蛋白溶解。