A Translational Bioinformatics Approach to Rescuing Synaptic and Neurophysiologic Dysfunction in Alzheimer's Disease

项目总监/首席调查员(最后、第一、中间)：Teich、Andrew、Franklin 项目摘要 这项提案的目标是确定FDA批准的化合物，这些化合物将挽救突触功能障碍 阿尔茨海默病(AD)。这一目标的动机是观察到公元前最早的事件之一是 突触功能障碍。在显微镜下的死后研究中，突触丢失与死前密切相关 认知状态，比斑块或缠绕更能预测死前的认知状态 病理学。面对这一证据，多个小组提出，突触功能障碍是 阿尔茨海默病的病理生理学。我们的实验室之前已经使用了新的数据挖掘技术来研究RNA表达 确定AD患者突触和神经生理功能障碍的主要调节因素的数据。这项计算工作 已经确定了转录调节因子，其在AD中的功能障碍被预测会导致 突触基因的表达(我们将这些转录调节因子称为“突触主调节因子”，或 突触MRS)。使用类似的技术，我们建议筛选FDA批准的化合物库中的它们 通过适当修改疾病相关的突触MRS来支持AD的突触功能的能力。在最后 在这个项目中，我们将有一份FDA批准的化合物清单，用于挽救突触MR功能障碍。虽然 这是该项目的主要终点，我们还将生成以下次要交付成果：1)RAT 神经元相互作用体，它预测大鼠神经元中每个转录调节因子的调节蛋白，2)人类 IPSC神经元相互作用组，它预测了人IPSC中每个转录调控因子的调节子 神经元，以及3)受FDA批准的化合物库影响的所有转录调控因子的列表。这些 其他可交付成果将用于其他神经系统疾病的药物发现。 OMB编号0925-0001/0002(03/16修订版批准至2018年10月31日)页面续格式页面

Program Director/Principal Investigator (Last, First, Middle): Teich, Andrew, Franklin Project Summary The goal of this proposal is to identify FDA approved compounds that will rescue synaptic dysfunction in Alzheimer’s Disease (AD). This goal is motivated by the observation that one of the earliest events in AD is synaptic dysfunction. In microscopic post-mortem studies, synaptic loss correlates strongly with pre-mortem cognitive status, and serves as a better predictor of pre-mortem cognitive status than either plaque or tangle pathology. Faced with this evidence, multiple groups have proposed that synaptic dysfunction is central to the pathophysiology of AD. Our laboratory has previously utilized novel datamining techniques on RNA expression data to identify master regulators of synaptic and neurophysiologic dysfunction in AD. This computational effort has identified transcriptional regulators whose dysfunction in AD is predicted to cause impairment in expression of synaptic genes (we refer to these transcriptional regulators as “synaptic master regulators,” or synaptic MRs). Using similar techniques, we propose to screen a library of FDA-approved compounds for their ability to support synaptic function in AD by appropriately modifying disease-relevant synaptic MRs. At the end of this project, we will have a list of FDA-approved compounds that rescue synaptic MR dysfunction. Although this is the primary endpoint of this project, we will also generate the following secondary deliverables; 1) A rat neuronal interactome, which predicts a regulon for every transcriptional regulator in rat neurons, 2) A human iPSC neuronal interactome, which predicts a regulon for every transcriptional regulator in human iPSC neurons, and 3) A list of all transcriptional regulators affected by a library of FDA-approved compounds. These additional deliverables will be usable for drug discovery of other neurologic diseases. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page