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.

项目概要 我们资助提案的目标是确定 FDA 批准的可挽救突触功能障碍的化合物 阿尔茨海默病 (AD) 中最早的事件之一是这一观察结果。 在显微镜死后研究中，突触丧失与死前密切相关。 认知状态，并且比斑块或缠结更能预测死前认知状态 面对这一证据，多个研究小组提出突触功能障碍是该疾病的核心。 AD 的病理生理学我们的实验室之前已经利用了 RNA 表达的新数据挖掘技术。 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。 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 使用类似的技术，我们建议筛选 FDA 批准的化合物库。 最后，通过适当修改与疾病相关的突触 MR 来支持 AD 中的突触功能。 在我们资助的提案中，我们将拥有一份 FDA 批准的可挽救突触 MR 功能障碍的化合物清单。 该补充剂的目标是扩大我们的药物筛选范围，以包括来自生物活性库的化合物 化合物，它将筛选比 FDA 通常发现的更广泛的治疗靶点 此外，我们将采用荧光筛选方法以更好地成像。 我们神经元中的轴突形态，这将是帮助我们消除化合物的附加信息 这会对神经突的完整性、复杂性和长度产生负面影响。 总之，这种补充剂将使我们能够 筛选更广泛的化合物，并将支持在我们的过程中收集额外的形态信息 筛选，这两者都将增强我们药物筛选的影响。