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

新的网络生物学方法重新定位 FDA 批准的阿尔茨海默病药物

基本信息

批准号：
10653036
负责人：
Kristen Jennifer Brennand
金额：
$ 84.7万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653036
关键词：
Acceleration Accounting Affect Alzheimer&apos s Disease Alzheimer&apos s disease therapy Animal Disease Models Binding Biological Models Biology Brain Cells Chronic Clinic Clinical Clinical Data Data Databases Dementia Development Disease Drug Combinations Epigenetic Process FDA approved Genetic Healthcare Systems Human In Vitro Individual Investigation Late Onset Alzheimer Disease Medicine Memory Loss Modeling Molecular Molecular Profiling Multiomic Data Mus Network-based Neurodegenerative Disorders Outcome Pathogenesis Pathogenicity Pathologic Pathway interactions Pharmaceutical Preparations Pharmacotherapy Phenotype Play Positioning Attribute Process Proteomics Regulation Role Sampling Structure Symptoms System Systems Biology Testing Therapeutic Intervention Therapeutic Research Tissues Treatment Efficacy brain cell clinical phenotype cognitive ability design differential expression drug development drug discovery drug efficacy efficacy evaluation efficacy testing efficacy validation experimental study high dimensionality in vivo induced pluripotent stem cell innovation molecular phenotype mouse model network models neuropathology novel novel therapeutics transcriptomics

项目摘要

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.

项目概要阿尔茨海默氏病 (AD)，特别是晚发性 AD，是痴呆症最常见的形式，占大约三分之二的痴呆症病例，其发病机制可能早在实际临床出现前几十年就开始了寻找改变疾病的治疗方法是最严格的治疗的首要目标。 AD 的治疗研究工作然而，AD 目前无法治愈，可用的疗法仅此而已。可以有效部分缓解特定的 AD 临床症状，但不能缓解其发作和/或进展。随着沉重的负担，及时开发有效的 AD 疗法的需求不断增长我们的医疗保健系统已达到关键水平，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进行开发，这些方法有潜力不仅呈现了通路-通路相互作用的全局景观，而且还提供了详细的分子整合大规模多组学的网络生物学方法的相互作用/调节电路。 AD 中的数据表明 AD 中存在差异调节的子网络，它调节不同的 AD 致病表型，往往包括大量的关键调节因子，因此药物和药物。可以整体调节此类子网络的组合对于治疗来说是最相关的在此应用中，我们建议开发新颖的技术。基于分子网络的药物重新定位方法来识别单个 FDA 批准的药物以及它们的组合有可能逆转 AD 的分子特征和网络状态。预测的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该项目将建立一个综合的原代细胞、人类 iPSC 衍生脑细胞和 AD 小鼠模型。平台由高度创新的系统和实验生物学组件组成，用于快速药物发现对于公元