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，这些化合物将挽救突触功能障碍阿尔茨海默氏病（AD）。突触功能障碍。认知状态，并且比斑块或纠缠一样，如验尸状态一样敏锐地预测病理学。 AD的病理生理学。数据识别AD中突触和神经自理生物学功能障碍的主调节剂已经确定了转录调节剂，其功能障碍被预测会导致损害突触基因的表达（我们将转录调节因子称为“突触主调节器”，突触MRS）。通过适当修饰疾病的突触MRS来支持AD中的突触功能在这个项目中，我们将有一系列抢救突触障碍的FDA申请清单。这是该项目的主要终点，我们还将生成以下辅助交付神经元相互作用组，可预测大鼠神经元中每个转录调节剂的调节剂，2）ahuman IPSC神经元相互作用组，它预测人IPSC中转录调节剂的调节神经元和3）所有转录调节器的列表受FDA培养基的影响。额外的可释放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