FUNCTIONAL ANALYSIS OF ASTROCYTE DERIVED APOE3 AND APOE4

描述：(改编自申请表)候选人(安妮·费根 Niven)获得了加州大学神经科学博士学位， 1992年在圣地亚哥，并有富有成效的研究调查的历史 发育中和受损神经系统中的神经元可塑性。这个 候选人在认知神经科学、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)培养了人们对 神经退行性疾病的病因学，特别是其发病机制(S) 哪种载脂蛋白E4是阿尔茨海默病的危险因素 (Ad)。由于已知载脂蛋白E是血浆的重要调节因子 胆固醇代谢，正确研究其在阿尔茨海默病中的作用以及 在正常的大脑中，将需要以下知识：1)AD，2)细胞生物学，以及 3)胆固醇/脂类代谢，应聘者几乎没有的领域 背景资料。拟议的计划将为候选人提供额外的 为了获得这三个领域的专业知识，需要进行一段时间的指导研究。 直接的职业目标是启动一项研究计划，调查 载脂蛋白E4与AD之间的联系。重要的是，科学和 在这些研究过程中获得的技术专门知识将使 实现她的长期目标的候选人；建立一个独立的， 神经科学的多学科研究生涯，重点是 神经元的生长和修复与神经退行性疾病有关。在……里面 这项拟议的研究假设脑源性脂蛋白 含有ApoE4的化合物在组成/结构上有本质上的不同 而不是那些含有载脂蛋白E3的人，这反过来会影响他们的能力 运输胆固醇/脂肪，和/或影响AB代谢。利用 通过星形胶质细胞表达人载脂蛋白E3或载脂蛋白E4的转基因小鼠 候选人将描述星形胶质细胞来源的成分/结构 脂蛋白颗粒和测试其运输胆固醇/脂类的能力 并在体内外影响AB代谢。大卫·M·霍尔茨曼医学博士 (Mentor)将提供AD、神经退行性疾病模型、 和细胞生物学；艾伦·施瓦茨，医学博士，博士(共同导师)，细胞生物学； 和咨询师，细胞生物学和脂类新陈代谢。WUSM，商务部 神经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群著名的教职员工致力于 用于研究、教育和培训。许多教育和技术 在WUSM向候选人提供的资源，与强大的 导师、合作导师和顾问的研究计划将提供 为实现她的职业目标所必需的全面训练。

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.