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

项目摘要 阿尔茨海默病(AD)，特别是迟发型AD，是痴呆症最常见的形式，占 大约三分之二的痴呆症病例，其发病机制可能在实际临床之前几十年就开始了 显化。寻找改善疾病的治疗方法是最严格的 对阿尔茨海默病的治疗研究。然而，阿尔茨海默病目前是无法治愈的，可用的治疗方法只有 对部分缓解选定的AD临床症状有效，但对其发病和/或进展无效。未被满足的人 随着沉重的负担，对及时开发治疗阿尔茨海默病的有效疗法的需求不断增长 对我们的医疗体系的影响达到了关键水平。迫切需要重振AD药物 利用系统生物学，特别是具有以下潜力的网络生物学方法进行开发 不仅展示了途径-途径相互作用的全球图景，而且还展示了详细的分子 AD背后的相互作用/调节电路。集成大规模多组学的网络生物学方法 AD中的数据表明，AD中调节不同AD的子网络是不同的 致病表型，往往包含大量的关键调控因子。因此，毒品和毒品 能够将这些子网络作为一个整体进行调制的组合是最适合治疗的 进行干预，并有更好的机会成功。在这一应用中，我们建议开发新的 基于分子网络的药物重新定位方法识别FDA批准的个别药物以及 它们的组合可能会逆转AD的分子特征和网络状态。一大笔钱 的预测药物和药物组合将在包括小鼠大脑在内的多个模型系统中进行测试 原代细胞、人iPSC来源的脑细胞和AD小鼠模型。该项目将建立一个综合性的 由高度创新的系统和实验生物学组件组成的快速药物发现平台 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.