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

项目负责人/主要研究者（最后，第一，中间）：Teich，Andrew，富兰克林 项目摘要 这项提案的目标是确定FDA批准的化合物，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AD中最早的事件之一是 突触功能障碍在显微镜下的死后研究中，突触丢失与死前死亡密切相关。 认知状态，并作为一个更好的预测死亡前的认知状态比无论是斑块或缠结 病理面对这一证据，多个研究小组提出，突触功能障碍是神经系统疾病的核心。 AD的病理生理学我们的实验室以前利用新的数据挖掘技术对RNA表达 数据来识别AD中突触和神经生理功能障碍的主要调节因子。这种计算工作 已经确定了转录调节因子，其在AD中的功能障碍预计会导致 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MR）。使用类似的技术，我们建议筛选FDA批准的化合物库， 通过适当修饰疾病相关的突触MR来支持AD中的突触功能的能力。 在这个项目中，我们将有一个FDA批准的拯救突触MR功能障碍的化合物清单。虽然 这是本项目的主要终点，我们还将生成以下次要可交付成果：1） 神经元相互作用组，其预测大鼠神经元中每个转录调节因子的调节子，2）人 iPSC神经元相互作用组，预测人类iPSC中每个转录调节因子的调节子 神经元，以及3）受FDA批准的化合物库影响的所有转录调节因子的列表。这些 其他可交付成果将可用于其他神经系统疾病的药物发现。 OMB编号0925-0001/0002（2016年3月修订版，批准至2018年10月31日）

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