CORE-- SCIENTIFIC

核心——科学

• 批准号: 3768581
• 负责人: T RAMABHADRAN
• 金额: --
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3768581
• 关键词: Alzheimer's disease; Baculoviridae; amyloid proteins; biomedical facility; drug /agent; drug design /synthesis /production; meeting /conference /symposium; molecular biology; neuropeptides

The overall goal of the Core project is to provide biochemical, pharmacological, and molecular biological support for the four component Projects of the proposed Program. Three Projects will focus on identification and development of chemical agents which influence the catabolic pathways of the amyloid precursor proteins (APPs). These studies will encompass the use of cell and tissue extracts (Project 1), intact transfected and normal cells (Project 2), and in vivo systems derived from normal (Project 2) and transgenic animals (Project 3). Projects proposed by two component groups will focus on cholinergic transmission. Project 3 will focus on defining the subtype(s) of the muscarinic acetylcholine receptor which are altered in aging and Alzheimer's disease, and the neuropeptide/modulator galanin will be studied in Project 4. A major function of the Core is to identify and obtain novel compounds from commercial sources and pharmaceutical companies for use by the component groups (particularly Projects 1 and 2, and in future years, also Project 3). These include inhibitors and stimulators of protein kinases and receptors; cation ionophores; ion channel blockers; lysosomotropic agents and agents which modify intracellular protein traffic. The Core will also serve as a liaison with industry in order to arrange for large-scale production and modification of any compounds that show desired properties. As an extension of its liaison activities, the Core will be responsible for organizing an annual meeting of an advisory committee composed of experts from academic laboratories with possible participation by selected representatives of the pharmaceutical industry. The Core will provide certain key reagents to various component projects. Projects 1 and 4 provide examples of these. Project 1 will be provided with purified holoAPP proteins and their fragments, overproduced using the baculovirus system. This will include site-directed mutagenesis, cell culture, protein purification, and microsequencing. The Core will provide peptide synthesis and recombinant DNA support to Project 4 for production of galanin analogs and galanin message associated peptide, GMAP.

核心项目的总体目标是提供生化、 四种成分的药理学和分子生物学支持 拟议计划的项目。 三个项目将重点 影响化学试剂的鉴定和开发 淀粉样前体蛋白（APP）的分解代谢途径。 这些研究 将包括使用完整的细胞和组织提取物（项目1） 转染细胞和正常细胞（项目 2），以及衍生自的体内系统 正常动物（项目2）和转基因动物（项目3）。 拟议项目 由两个组成部分组成的小组将重点关注胆碱能传递。 项目3 将重点定义毒蕈碱乙酰胆碱的亚型 受体在衰老和阿尔茨海默氏病中发生改变， 神经肽/调节剂甘丙肽将在项目 4 中进行研究。 核心的一个主要功能是识别和获取新化合物 该组件使用的商业来源和制药公司 组（特别是项目 1 和 2，以及在未来几年，项目 3）。 这些包括蛋白激酶的抑制剂和刺激剂以及 受体；阳离子离子载体；离子通道阻滞剂；溶酶体药物 以及改变细胞内蛋白质运输的试剂。 核心还将 作为与工业界的联络，以安排大规模的 生产和修饰任何具有所需特性的化合物。 作为其联络活动的延伸，核心将负责 组织由专家组成的咨询委员会的年度会议 来自学术实验室，并可能由选定的参与 医药行业的代表。 该核心将为各个组成项目提供某些关键试剂。 项目 1 和 4 提供了这些示例。 将提供项目1 纯化的 HoloAPP 蛋白及其片段，使用 杆状病毒系统。 这将包括定点诱变、细胞 培养、蛋白质纯化和微测序。 核心将提供 为项目 4 的生产提供肽合成和重组 DNA 支持 甘丙肽类似物和甘丙肽信息相关肽，GMAP。