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) 是一种重要的 胆固醇转运系统的蛋白质。 ApoE 负责 通过脂蛋白从循环中清除脂蛋白残余物 受体，有助于胆固醇稳态，并防止 动脉粥样硬化。 ApoE 还被证明具有其他功能 有助于胆固醇和甘油三酯稳态，包括 VLDL 甘油三酯分泌和极低密度脂蛋白脂解，这两个过程可能会影响 血浆甘油三酯水平。这是我们的假设，它得到了支持 初步数据，apoE 的羧基末端结构域负责 apoE过度表达引起的高甘油三酯血症。我们也 假设羧基末端 apoE 变体的过度表达可以保护 来自动脉粥样硬化。我们的具体目标是：1）利用腺病毒介导的基因 转移以及转基因小鼠阐明 apoE 在 甘油三酯稳态并建立 apoE 诱导机制 体内高甘油三酯血症。 2) 利用腺病毒介导的基因转移 不同的 apoE 形式（在适当的受体缺陷小鼠模型中） 阐明 apoE 受体在体内和体内胆固醇清除中的作用 体外。将用于基因转移的小鼠模型是apoE-/-， LDLR-/-、肝脏特异性 LRP-/- 小鼠以及这些基因之间的杂交 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 使用腺相关病毒载体（AAV-apoE）治疗高甘油三酯血症和 转基因小鼠以纠正高胆固醇血症和动脉粥样硬化 apoE 缺陷小鼠的概况。这一具体目标将探索以下能力： 选择的 apoE 的截短和突变形式不会诱导 高甘油三酯血症可预防动脉粥样硬化。我们期望 apoE 形成 可以清除胆固醇和甘油三酯并预防动脉粥样硬化 可能在不久的将来提供新的治疗工具来纠正 残余物清除障碍。