APOE RECYCLING: Cell Biology and Physiologic Relevance

描述（由申请人提供）：载脂蛋白（apo）E起关键作用 在脂质和脂蛋白代谢中的作用， 细胞内。我们实验室最近的研究表明， 内化的apoE可以免于降解和再循环，这一过程 能够使apoE影响细胞功能。这是我们的目标 资助界定载脂蛋白E再循环和再分泌机制， 解决其生理相关性。这项提案将测试工作 假设一小部分内化的apoE在细胞中免于降解， 细胞和回收，提供了一种机制，其中蛋白质是关键的， 许多生物过程可以最大化其对细胞功能的影响。这 假设将通过以下具体目标进行检验：具体目标#1。 为了确定apoE再循环是否依赖于细胞进入点， 与apoE相关的脂蛋白颗粒。这些研究将测试 假设内化apoE的倾向和潜在的 回收取决于apoE所在的颗粒和 进入细胞。具体目标#2为了定义细胞内的运输 apoE循环途径。这些研究将验证apoE 通过分泌途径，特别是通过高尔基体 设备.具体目标#3定义apoE的生理相关性 回收利用。这些研究将检验这样一个假设，即回收利用提供了 apoE影响细胞功能，特别是脂质和 脂蛋白代谢、分泌捕获和胆固醇流出。这些 研究将主要集中在肝细胞的apoE再循环，但也将 扩展到巨噬细胞，这是一种细胞类型，apoE循环对 功能可能与动脉粥样硬化形成密切相关。

DESCRIPTION (provided by applicant): Apolipoprotein (apo) E plays critical roles in lipid and lipoprotein metabolism both extracellularly and intracellularly. Recent studies in our laboratories have shown that internalized apoE may be spared from degradation and recycled, a process that would enable apoE to impact cellular functions. It is the objective of this grant to define the mechanisms of apoE recycling and resecretion and to start addressing its physiologic relevance. This proposal will test the working hypothesis that a fraction of internalized apoE is spared degradation in the cell and recycled, providing a mechanism whereby a protein that is critical for many biological processes can maximize its impact on cellular functions. This hypothesis will be tested through the following specific aims: Specific Aim #1. To determine if apoE recycling is dependent upon cellular entry point or the lipoprotein particle with which apoE is associated. These studies will test the hypothesis that the disposition of internalized apoE and the potential for recycling are dependent on the particle on which apoE resides and the point of entry into the cell. Specific Aim #2. To define the intracellular trafficking pathway of recycling apoE. These studies will test the hypothesis that apoE recycles through the secretory pathway, specifically through the Golgi apparatus. Specific Aim #3. To define the physiologic relevance of apoE recycling. These studies will test the hypothesis that recycling provides a pathway for apoE to impact cellular functions, specifically lipid and lipoprotein metabolism, secretion-capture, and cholesterol efflux. These studies will primarily focus on apoE recycling by the hepatocyte, but will also expand to the macrophage, a cell type for which the impact of apoE recycling on function may be of great relevance to atherogenesis.