Interdisciplinary Approach to Alzheimer Drug Discovery

阿尔茨海默病药物发现的跨学科方法

• 批准号: 7279295
• 负责人: SAMUEL E. GANDY
• 金额: $ 155.45万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7279295
• 关键词: Interdisciplinary; Approach; Alzheimer; Drug; Discovery

DESCRIPTION (provided by applicant): The history and current activity of this Program Project attest to its focus on discovery of druggable anti-Abeta oligomer targets by identifying the molecular bases for the phenomena that appear important for Abeta oligomerization and accumulation (e.g., protein folding, protein levels, etc.). The theme of all Projects in the A2 revision of this competitive renewal focuses on lipoprotein regulation of APP and Abeta metabolism at the cell surface. Growing evidence indicates that low and high density lipoproteins control two limbs of the APP/Abeta metabolic scheme: Apolipoproteins E and J modulate Abeta clearance via a variety of surface receptors, while LDL and HDL activate signalling pathways via the low density lipoprotein receptor-like protein (LRP) that feed back on the cell surface and cause activation or inhibition of APP metabolism by alpha-secretase ("ectodomain shedding"). Major questions posed by each Project are: (Project by Gandy) Statins activate alpha-secretase via ROCK. How do lipoproteins modulate this signal following binding to LRP? What are the phospho-state-specific modulators of APP ectodomain shedding? (Project by Ghiso): How do conformational transitions of Abeta and interactions of oligomeric Abeta with Apolipoproteins/Apolipoprotein receptors affect protein catabolism within brain cells, resulting in Abeta accumulation and the concomitant formation of the amyloid deposits seen in Alzheimer's? (Project by Buxbaum): What role(s) do the major ApoE receptors play in Abeta metabolism? (Project by Martins):. Can ApoE isoform-specific effects on Abeta clearance be demonstrated in vitro or in vivo? What is the role of ApoE protein level in brain or in the circulation? These questions will be answered using a highly collaborative approach and a range of experimental systems, including purified proteins, expression of foreign genes in primary CNS cells, and genetic induction of excessive or deficient levels of CNS proteins. Ultimately, data from such approaches will inform the development of effective anti-amyloid agents, which, in turn, will provide the ultimate test of the role of Abeta oligomerization in Alzheimer's disease.

描述(由申请人提供)：该计划项目的历史和目前的活动证明了它的重点是通过确定对Abeta齐聚和积累(例如，蛋白质折叠、蛋白质水平等)重要的现象的分子基础来发现可药物的抗Abeta寡聚体靶标。本次竞争性更新A2版本中所有项目的主题都集中在APP的脂蛋白调节和细胞表面的Abeta代谢。越来越多的证据表明，低密度脂蛋白和高密度脂蛋白控制着APP/Aβ代谢机制的两个分支：载脂蛋白E和J通过多种表面受体调节Aβ的清除，而低密度脂蛋白和高密度脂蛋白通过低密度脂蛋白受体样蛋白(LRP)激活信号通路，该信号通路反馈到细胞表面，通过α-分泌酶引起APP代谢的激活或抑制(“胞外结构域脱落”)。每个项目提出的主要问题是：(甘迪项目)他汀类药物通过岩石激活α-分泌酶。脂蛋白与LRP结合后如何调节这一信号？APP胞外结构域脱落的磷酸状态特异性调节剂是什么？(由Ghiso项目)：Abeta的构象转变和寡聚体Abeta与载脂蛋白/载脂蛋白受体的相互作用如何影响脑细胞内的蛋白质分解代谢，导致Abeta积聚和阿尔茨海默病患者淀粉样沉积的伴随形成？(由Buxbaum项目)：主要的载脂蛋白E受体在Abeta代谢中扮演什么角色(S)？(Martins项目)：。载脂蛋白E亚型对Abeta清除的特异性作用能在体外或体内得到证实吗？载脂蛋白E蛋白水平在脑或循环中的作用是什么？这些问题将通过高度协作的方法和一系列实验系统来回答，包括纯化蛋白、在原代中枢神经系统细胞中表达外源基因，以及对过量或不足水平的中枢神经系统蛋白质的遗传诱导。最终，来自这种方法的数据将为有效的抗淀粉样蛋白药物的开发提供信息，这反过来将为Abeta寡聚在阿尔茨海默病中的作用提供最终测试。