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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：
10260473
负责人：
Kristen Jennifer Brennand
金额：
$ 84.75万
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/10260473
关键词：
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 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 Process Proteomics Regulation Role Sampling Structure Symptoms System Systems Biology Testing Therapeutic Human Experimentation Therapeutic Intervention Time Tissues Treatment Efficacy base 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 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。