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

• 批准号: 10320653
• 负责人: Andrew Franklin Teich
• 金额: $ 40.45万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320653
• 关键词: Alzheimer' s Disease; Alzheimer' s disease patient; Autopsy; Bioinformatics; Cognitive; Data; Dementia; Disease; Drug Screening; Event; FDA approved; Functional disorder; Funding; Genes; Genetic Transcription; Goals; Image; Impairment; Laboratories; Length; Libraries; Methods; Microscopic; Morphology; Neurites; Neurofibrillary Tangles; Neurons; Pathology; Synapses; Techniques; Western World; data mining; loss of function; negative affect; neurophysiology; novel; screening; synaptic function; therapeutic target

Project Summary The goal of our funded 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 our funded proposal, we will have a list of FDA-approved compounds that rescue synaptic MR dysfunction. The goal of this supplement is to expand our drug screen to include compounds from a library of bioactive compounds, which will screen for a wider range of therapeutic targets than is typically found in an FDA- approved compound library. In addition, we will incorporate a fluorescent screening method to better image neurite morphology in our neurons, which will be additive information that will help us eliminate compounds that that negatively affect neurite integrity, complexity, and length. In summary, this supplement will allow us to screen a wider range of compounds and will support gathering additional morphological information during our screen, both of which will enhance the impact of our drug screen.

项目摘要 我们资助的提案的目标是确定FDA批准的化合物，将拯救突触功能障碍 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。 在我们资助的提案中，我们将有一个FDA批准的化合物清单，可以挽救突触MR功能障碍。 这一补充的目标是扩大我们的药物筛选，包括从生物活性化合物库化合物 化合物，这将筛选更广泛的治疗目标比通常发现在FDA- 批准的复合图书馆。此外，我们将采用荧光筛选方法，以更好地成像 我们神经元中的神经突形态，这将是帮助我们消除化合物的附加信息， 对神经突完整性、复杂性和长度产生负面影响。总之，这一补充将使我们能够 筛选更广泛的化合物，并将支持收集更多的形态信息，在我们的 这两种方法都将增强我们药物筛选的影响。