SCEINTIFIC CORE

阿尔茨海默病（AD）神经病理学改变及其分子和细胞学改变的研究 它们背后的变化已经产生了大量关于这种毁灭性疾病病因学的信息。 疾病项目1-3中概述的综合研究将在现有知识的基础上扩展， 对神经元细胞进行严格的细胞生物学、分子学、生物化学、行为学和电生理学研究 在体外和几种AD小鼠模型中。这些研究有可能提供更深入的了解， AD的病因学以及阐明AD治疗的可能的新靶点。科学核心将是一个 该中心致力于促进项目1-3中提出的需要使用初级 神经元和器官型培养物、转基因动物、免疫试剂和酵母- 重组γ-分泌酶这一集中设施的存在将确保 项目1-3将以最及时和最具成本效益的方式完成。许多研究建议， 这项计划项目资助将需要使用高质量的神经元培养物来验证最初的发现 转化的细胞系。在具体目标I中，核心将负责执行日常任务 参与项目1-3所需的原代神经元和器官型培养物的制备。因为所有 项目1-3的发现最终将在完整的动物身上得到验证和测试， 这些项目中概述的生物多样性还要求繁殖和饲养转基因动物。 因此，转基因小鼠的培育和维持是第二个具体目标的核心。为了帮助 新的蛋白质-蛋白质相互作用，蛋白质定位和蛋白质磷酸化的表征， 科学核心将是新的多克隆抗体的关键来源，包括磷酸化状态- 特异性抗体，如特定目标III中所述。最后，γ-分泌酶活性的重建， 用于遗传操作和筛选的简单真核生物巴斯德毕赤酵母是Specific Aim IV。

Studies of the neuropathological alterations seen in Alzheimer's Disease (AD) and the molecular and cellular changes underlying them have yielded a wealth of information regarding the etiology of this devastating disease. The combined studies outlined in Projects 1-3 will extend upon this existing knowledge with rigorous cell biological, molecular, biochemical, behavioral, and electrophysiological studies of neuronal cells in vitro and in several mouse models of AD. These studies have the potential to provide greater insight into the etiology of AD as well as to elucidate possible novel targets for AD therapy. The Scientific Core will be a center devoted to facilitating the experiments proposed in Projects 1-3 that require the use of primary neuronal and organotypic cultures, genetically modified animals, immunological reagents, and yeast- reconstituted y-secretase. The existence of this centralized facility will ensure that the experiments outlined in Projects 1-3 will be completed in the most timely and cost-effective manner. Many of the studies proposed in this Program Project Grant will require the use of high-quality neuronal cultures to validate initial findings from transformed cell lines. In Specific Aim I, the Core will be responsible for performing the routine tasks involved in the preparation of primary neuronal and organotypic cultures needed by Projects 1-3. As all of the findings of Projects 1-3 will ultimately be validated and tested in intact animals, the experiments outlined in these Projects will also require the breeding and maintenance of genetically modified animals. Thus the breeding and maintenance of transgenic mice is Specific Aim II of the Core. In order to aid in the characterization of new protein-protein interactions, protein localization, and protein phosphorylation, the Scientific Core will be a keysource of new polyclonal antibodies, including phosphorylation state- specific antibodies, as described in Specific Aim III. Finally, the reconstitution of y-secretaseactivity in the simple eukaryote P. pastoris for genetic manipulation and screening is Specific Aim IV.