ApoE in Cholesterol and Triglyceride Homeostasis

描述(申请人提供)：载脂蛋白E(ApoE)是一种重要的 胆固醇运输系统的蛋白质。APOE负责 通过脂蛋白清除循环中的脂蛋白残留物 受体，有助于胆固醇稳态，并保护 动脉硬化。APOE还被证明具有其他功能， 有助于胆固醇和甘油三酯的稳态，包括极低密度脂蛋白 甘油三酯分泌和极低密度脂蛋白脂解，这两个过程可能影响 血浆甘油三酯水平。这是我们的假设，它得到了 初步数据，载脂蛋白E的羧基末端结构域负责 载脂蛋白E过度表达所致的高甘油三酯血症。我们也 假设羧基末端载脂蛋白E变异体的过度表达可能保护 死于动脉粥样硬化。我们的具体目标是：1)使用腺病毒介导的基因 转移以及转基因小鼠以阐明载脂蛋白E在 甘油三酯稳态与载脂蛋白E诱导机制的建立 体内高甘油三酯血症。2)用腺病毒载体介导的基因转移 不同的载脂蛋白E形式(在适当的受体缺陷小鼠模型中) 阐明载脂蛋白E受体在体内和体内胆固醇清除中的作用 体外培养。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确定配体的特异性 不同的受体。3)表达不诱导的长期载脂蛋白E形式 用腺相关病毒载体(AAV-apoE)治疗高甘油三酯血症 转基因小鼠以纠正高胆固醇血症和动脉粥样硬化 载脂蛋白E缺陷小鼠的概况。这一具体目标将探索 选择不能诱导的apoE的截短和突变形式 预防动脉粥样硬化的高甘油三酯血症。我们预计apoE表单 可以清除胆固醇和甘油三酯，防止动脉粥样硬化 可能在不久的将来提供新的治疗工具，用于纠正 残留物清除障碍。

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.