FUNCTIONAL ANALYSIS OF ASTROCYTE DERIVED APOE3 AND APOE4

星形胶质细胞来源的 APOE3 和 APOE4 的功能分析

• 批准号: 6043006
• 负责人: Anne Fagan
• 金额: $ 8.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-15 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6043006
• 关键词: Alzheimer's disease; apolipoprotein E; astrocytes; blood lipoprotein metabolism; blood lipoprotein transport; brain metabolism; cerebrospinal fluid; cholesterol; clinical research; denervation; electron microscopy; experimental brain lesion; gel filtration chromatography; genetically modified animals; human subject; laboratory mouse; neural degeneration; polymerase chain reaction; protein isoforms; protein structure; tissue /cell culture

DESCRIPTION: (Adapted from the application) The candidate (Anne Fagan Niven) received her Ph.D. in Neuroscience from the University of California, San Diego in 1992, and has a history of productive research investigating neuronal plasticity in the developing and injured nervous system. The candidate has expertise in cognitive neuroscience, neuronal development, neuroanatomy, and molecular neurobiology. Recent work at Washington University School of Medicine (WUSM) has fostered an interest in the etiology of neurodegenerative disease, in particular, the mechanism(s) by which apolipoprotein (ApoE) E4 is a risk factor for Alzheimer's disease (AD). Since ApoE is known to be an important regulator of plasma cholesterol metabolism, proper investigation of its role in AD, as well as in the normal brain, will require knowledge of: 1) AD, 2) cell biology, and 3) cholesterol/lipid metabolism, areas in which the candidate has little background. The proposed plan will provide the candidate with an additional period of mentored research in order to gain expertise in these three areas. The immediate career goal is to initiate a research program investigating the connection between ApoE4 and AD. Importantly, the scientific and technical expertise gained in the course of these studies will allow the candidate to attain her long-term goal; to establish an independent, multidisciplinary research career in neuroscience, with an emphasis on neuronal growth and repair as it relates to neurodegenerative disease. In the proposed study, it is hypothesized that brain-derived lipoproteins containing ApoE4 are inherently different in their composition/structure than those containing ApoE3, which in turn affects their ability to transport cholesterol/lipid, and/or affect AB metabolism. Utilizing transgenic mice which express human ApoE3 or ApoE4 by astrocytes, the candidate will characterize the composition/structure of astrocyte-derived lipoprotein particles and test their ability to transport cholesterol/lipid and affect AB metabolism in vitro and in vivo. David M. Holtzman, M.D (mentor) will provide training in AD, models of neurodegenerative disease, and cell biology; Alan L. Schwartz, M.D., Ph.D. (co-mentor), cell biology; and consultants, cell biology and lipid metabolism. WUSM, the Department of Neurology, and its associated Alzheimer's Disease Research Center has well-established research programs and a renowned group of faculty committed to research, education, and training. The many educational and technical resources available to the candidate at WUSM, in combination with the strong research programs of the mentor, co-mentor, and consultants, will provide the comprehensive training necessary to achieve her career goals.

描述：（改编自应用程序）候选人（安妮费根 Niven）获得了博士学位。来自加州大学的神经科学教授， 1992年在圣地亚哥，并有一个富有成效的研究调查的历史， 发育和受损神经系统中的神经元可塑性。 的 候选人具有认知神经科学，神经元发育， 神经解剖学和分子神经生物学。 最近在华盛顿的工作 大学医学院（WUSM）培养了对 神经退行性疾病的病因学，特别是， 其中载脂蛋白（ApoE）E4是阿尔茨海默病的危险因素 （AD）。 由于已知ApoE是血浆中重要的调节因子， 胆固醇代谢，适当研究其在AD中的作用，以及 在正常大脑中，将需要以下知识：1）AD，2）细胞生物学， 3)胆固醇/脂质代谢，候选人几乎没有 背景 拟议的计划将为候选人提供额外的 一段时间的指导研究，以获得在这三个领域的专业知识。 近期的职业目标是启动一项研究计划， ApoE 4与AD的关系 重要的是，科学和 在这些研究过程中获得的技术专长将使 候选人实现她的长期目标;建立一个独立的， 神经科学的多学科研究生涯，重点是 神经元生长和修复，因为它涉及神经退行性疾病。 在 在这项拟议的研究中，假设脑源性脂蛋白 含有ApoE 4的蛋白质在其组成/结构上固有地不同 而ApoE 3则会影响他们的能力， 转运胆固醇/脂质和/或影响AB代谢。 利用 通过星形胶质细胞表达人ApoE 3或ApoE 4的转基因小鼠， 候选人将表征星形胶质细胞衍生的 脂蛋白颗粒，并测试其转运胆固醇/脂质的能力 并影响体内外AB代谢。 大卫M. Holtzman，医学博士 （导师）将提供AD，神经退行性疾病模型， 和细胞生物学; Schwartz，医学博士，博士（共同导师），细胞生物学; 和顾问，细胞生物学和脂质代谢。 WUSM， 神经病学及其相关的阿尔茨海默病研究中心 完善的研究计划和一个著名的教师群体致力于 研究、教育和培训。 许多教育和技术 在WUSM候选人可用的资源，结合强大的 导师，共同导师和顾问的研究计划，将提供 实现职业目标所需的全面培训。