Novel Network Biology Approaches to Reposition FDA-approved Drugs for Alzheimer's Disease

项目摘要 阿尔茨海默氏病（AD），特别是迟发性AD，是痴呆的最常见形式，占痴呆的20%。 大约三分之二的痴呆病例，其发病机制可能在其实际临床之前几十年就开始了。 表现。寻找疾病修饰治疗是最严格的医学研究的主要目标。 AD的治疗研究工作。然而，AD目前是不可治愈的，并且可用的疗法仅限于 有效地部分缓解选定的AD临床症状，但不缓解其发作和/或进展。未满足的 随着负担的沉重，及时开发有效的AD疗法的需求不断增长 我们的医疗系统达到了临界水平。迫切需要重振AD药物 利用系统生物学，特别是网络生物学方法， 不仅呈现了途径-途径相互作用的全局景观， 相互作用/调节电路的基础AD。整合大规模多组学的网络生物学方法 AD的数据表明，AD中调节不同AD的差异调节子网络 致病表型通常包括大量的关键调节因子。因此，毒品和毒品 可以调节这些子网络作为一个整体的组合是最相关的治疗 更好的介入，更有可能成功。在本申请中，我们提出开发新颖的 基于分子网络的药物重新定位方法，以识别单个FDA批准的药物， 它们的组合可以潜在地逆转AD的分子特征和网络状态。大量 预测的药物和药物组合将在多个模型系统中进行测试，包括小鼠大脑 原代细胞、人iPSC衍生的脑细胞和AD小鼠模型。该项目将建立一个综合 由高度创新的系统和实验生物学组件组成的平台，用于快速药物发现 对于AD。

Project Summary Alzheimer's disease (AD), in particular la‐te onset AD, is the most common form of dementia, accounting for about two thirds of all the dementia cases, and its pathogenesis may start decades early before its actual clinic manifestation. The search for disease modifying treatments is the primary objective of most rigorous therapeutic research efforts on AD. However, AD is currently incurable and available therapies are only effective in partially alleviating selected AD clinical symptoms, but not its onset and/or progression. The unmet need for the timely development of potent therapies for AD has been constantly growing with the heavy burden on our healthcare system reaching a critical level. There is an urgent need to reinvigorate AD drug development by utilizing systems biology, especially network biology approaches which have the potential to present not only global landscape of pathway-pathway interactions but also detailed molecular interaction/regulation circuits underlying AD. Network biology approaches to integrate large-scale multi-omics data in AD have demonstrated that differentially regulated subnetworks in AD, which regulate diverse AD pathogenic phenotypes, often include a large number of key regulators. Therefore, drugs and drug combinations that can modulate such subnetworks as a whole are the most pertinent for therapeutic intervention and have better chance to be successful. In this application, we propose to develop novel molecular network based drug repositioning approaches to identify individual FDA approved drugs as well as their combinations that can potentially reverse molecular signatures and network states of AD. A large number of predicted drugs and drug combinations will be tested in multiple model systems including mouse brain primary cells, human iPSC derived brain cells and AD mouse models. This project will establish an integrative platform comprised of highly innovative systems and experimental biology components for rapid drug discovery for AD.