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

挽救阿尔茨海默病突触和神经生理功能障碍的转化生物信息学方法

基本信息

批准号：
10441481
负责人：
Andrew Franklin Teich
金额：
$ 39.43万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10441481
关键词：
Adult Affect Alzheimer&apos s Disease Alzheimer&apos s disease patient Autopsy Bioinformatics Biological Models Biology Cell Line Cognitive Data Dementia Disease Down-Regulation Drug Screening Event FDA approved Functional disorder Gene Expression Genes Genetic Transcription Goals Human Impairment Laboratories Libraries London Methods Microscopic Modeling Morbidity - disease rate Mutation Neurofibrillary Tangles Neurons Pathology Persons Principal Investigator Rattus Regulon Research Synapses Techniques Technology Testing Therapeutic Up-Regulation Western World Work base cell type cost data mining differential expression drug discovery induced pluripotent stem cell interest knock-down loss of function mortality nervous system disorder neurophysiology novel overexpression primary endpoint programs screening synaptic function transcriptome transcriptome sequencing

项目摘要

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

计划总监/首席研究员（最后，第一，中间）：Teich，Andrew，Franklin 项目摘要该提案的目的是确定FDA批准的化合物，以挽救突触功能障碍阿尔茨海默氏病（AD）。这一目标是由于观察到广告中最早的事件之一是突触功能障碍。在微观验尸研究中，突触损失与验尸密切相关认知状况，比斑块或纠结更好地预测了验尸状态的更好的预测指标病理。面对这些证据，多个小组提出突触功能障碍是 AD的病理生理学。我们的实验室以前已经利用了有关RNA表达的新型数据设计技术数据以识别AD中突触和神经生理功能障碍的主调节剂。这项计算工作已经确定了转录调节剂，其AD功能障碍预计会导致损害突触基因的表达（我们将这些转录调节因子称为“突触主调节器”，或突触MRS）。使用类似的技术，我们建议筛选FDA批准的化合物的库通过适当修改与疾病相关的合成MRS来支持AD中的合成功能的能力。在最后在该项目中，我们将有一份FDA批准的化合物列表，这些化合物可以挽救突触功能障碍。虽然这是该项目的主要端点，我们还将生成以下次级可交付成果。 1）大鼠神经元相互作用组，它可以预测大鼠神经元中每个转录调节剂的调节，2） IPSC神经元相互作用组，预测人IPSC中每个转录调节剂的调节神经元和3）所有转录调节器的列表，该列表受FDA批准化合物库影响的所有转录调节器。这些其他可交付成果可用于药物发现其他神经系统疾病。 OMB编号0925-0001/0002（Rev. 03/16批准通过10/31/2018）页面延续格式页面