ApoE in Cholesterol and Triglyceride Homeostasis

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，并保护 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VLDL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， 初步数据表明，apoE的羧基末端结构域负责 apoE过表达引起的高脂血症。我们也 假设羧基末端apoE变体过表达可以保护 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工程技术， 转移以及转基因小鼠，以阐明apoE在 甘油三酯稳态和建立apoE诱导的机制 体内高胆固醇血症。2)利用腺病毒介导的基因转移技术， 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-/-小鼠以及这些小鼠之间的杂交 转移和受体结合研究将确定配体特异性， 不同的受体。3)表达长期的apoE形式， 使用腺相关病毒载体（AAV-apoE）治疗高脂血症， 转基因小鼠，以纠正高胆固醇血症和动脉粥样硬化 apoE缺陷小鼠的特征。这一具体目标将探索的能力， 选择的apoE的截短和突变形式，其不诱导 预防动脉粥样硬化。我们认为apoE 它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， 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.