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A-I是血浆高密度脂蛋白的主要载脂蛋白 脂蛋白（HDL）。 血浆脂蛋白在胆固醇中起关键作用 代谢和重要因素，确定这些人的风险 动脉粥样硬化、中风和心血管疾病。 人士 高水平的循环HDL是在较低的风险，为并发症 动脉粥样硬化 已经鉴定了载脂蛋白A-I的许多功能， 有助于其有益的特性。 其中包括apo的容量 A-I：1）激活血浆中胆固醇的酶， 卵磷脂：胆固醇酰基转移酶（LCAT），B）介导胆固醇 递送至类固醇生成组织，c）促进胆固醇从 某些非肝的外周细胞，如负载胆固醇酯的 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，载脂蛋白A-I在血管内皮细胞中起重要作用。 生物学和胆固醇代谢。 载脂蛋白A-I的一级结构是 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，载脂蛋白结构和功能之间的关系将 被探索。 将研究四种功能，包括LCAT激活， 胆固醇输送到类固醇生成细胞，胆固醇从 巨噬细胞，以及纤维蛋白溶解的增强。 一个现有的apo小组 A-I特异性单克隆抗体，其针对独特的 将筛选apo A-I上的区域，以确定其阻断以下各项的能力： 这些载脂蛋白A-I功能。 当发现抗体干扰了 特定的功能，代表功能的片段 将检测载脂蛋白A-I的重要区域的能力， 模拟或阻断载脂蛋白A-I功能。 这些研究将验证这一假设 载脂蛋白A-I上的特定结构区域可以被鉴定为 负责其众多功能中的每一项。 此外，成功的 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， 激活LCAT，细胞相互作用，以及增强 载脂蛋白A-I纤溶。