ApoE in Cholesterol and Triglyceride Homeostasis

ApoE 在胆固醇和甘油三酯稳态中的作用

• 批准号: 6796773
• 负责人: VASSILIS I ZANNIS
• 金额: $ 28.53万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6796773
• 关键词: apolipoprotein E; atherosclerosis; blood lipoprotein metabolism; blood lipoprotein transport; cardiovascular disorder therapy; cholesterol; gene therapy; genetically modified animals; laboratory mouse; nonhuman therapy evaluation; protein structure function; transfection; triglycerides

DESCRIPTION (provided by applicant): Apolipoprotein E (apoE) is an important protein of the cholesterol transport system. ApoE is responsible for the clearance of lipoprotein remnants from the circulation via lipoprotein receptors, contributes to cholesterol homeostasis, and protects from atherosclerosis. ApoE has also been shown to have other functions which contribute to cholesterol and triglyceride homeostasis, including VLDL triglyceride secretion and VLDL lipolysis, two processes which may affect plasma triglyceride levels. It is our hypothesis, which is supported by preliminary data, that the carboxy terminal domain of apoE is responsible for the hypertriglyceridemia which is induced by overexpression of apoE. We also hypothesize that overexpression of carboxy terminal apoE variants may protect from atherosclerosis. Our specific aims are: 1) To use adenovirus-mediated gene transfer as well as transgenic mice to elucidate the role of apoE in triglyceride homeostasis and establish the mechanism of apoE-induced hypertriglyceridemia in vivo. 2) To use adenovirus-mediated gene transfer of different apoE forms (in appropriate receptor-deficient mouse models) to elucidate the role of apoE receptors in cholesterol clearance in vivo and in vitro. The mouse models that will be utilized for gene transfer are apoE-/-, LDLR-/-, liver-specific LRP-/- mice as well as crosses among these The gene transfer and receptor binding studies will define the ligand speciflcities for different receptors. 3) To express long-term apoE forms that do not induce hypertriglyceridemia using adenoassociated viral vectors (AAV-apoE) and transgenic mice in order to correct the hypercholesterolemic and atherogenic profile of apoE-deficient mice. This specific aim will explore the ability of selected truncated and mutant forms of apoE that do not induce hypertriglyceridemia to protect from atherosclerosis. We expect that apoE forms that can clear cholesterol and triglycerides and protect from atherosclerosis may provide new therapeutic tools in the near future for the correction of remnant removal disorders.

描述（由申请人提供）：载脂蛋白E（APOE）很重要 胆固醇运输系统的蛋白质。 Apoe负责 通过脂蛋白从循环中清除脂蛋白残留物 受体，有助于胆固醇稳态，并保护 动脉粥样硬化。 APOE还显示具有其他功能 胆固醇和甘油三酸酯稳态，包括VLDL 甘油三酸酯的分泌和VLDL脂解，两个可能影响的过程 血浆甘油三酸酯水平。这是我们的假设，得到了 初步数据，APOE的羧基终端域负责 由APOE过表达诱导的高甘油三酯血症。我们也是 假设羧基终端APOE变体的过表达可以保护 来自动脉粥样硬化。我们的具体目的是：1）使用腺病毒介导的基因 转移和转基因小鼠以阐明ApoE在 甘油三酸酯稳态并建立APOE诱导的机制 体内高甘油三酯血症。 2）使用腺病毒介导的基因转移 不同的APOE形式（在适当的受体鼠标模型中） 阐明APOE受体在体内和在体内胆固醇清除率中的作用 体外。将用于基因转移的小鼠模型是apoE - / - ， LDLR - / - ，肝特异性LRP - / - 小鼠以及这些基因中的交叉 转移和受体结合研究将定义配体特异性 不同的受体。 3）表达不诱导的长期APOE形式 使用腺关系的病毒载体（AAV-APOE）和 转基因小鼠以纠正高胆固醇和动脉粥样硬化 APOE缺陷小鼠的轮廓。这个具体目标将探讨 不诱导的APOE的选定截短和突变形式 高甘油三酯血症可免受动脉粥样硬化。我们希望Apoe形成 可以清除胆固醇和甘油三酸酯并防止动脉粥样硬化 在不久的将来可以提供新的治疗工具 残余疾病。