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：
10451659
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/10451659
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氏病（AD），尤其是LA -TE发作广告，是最常见的痴呆症形式大约三分之二的痴呆症病例，其发病机理可能在其实际诊所之前几十年开始表现。寻找修改疾病的治疗是最严格的主要目标 AD的治疗研究工作。但是，广告目前无法治愈，可用的疗法只是有效可部分缓解选定的AD临床症状，但无效，但无效。未满足随着沉重负担，需要及时开发有效的广告疗法在我们的医疗保健系统上达到关键水平。迫切需要重振AD药物通过使用系统生物学的开发，尤其是具有潜力的网络生物学方法不仅存在通路通道相互作用的全球景观，还存在详细的分子 AD上的相互作用/调节电路。网络生物学方法以整合大规模多摩斯 AD中的数据表明，AD中对不同的子网进行了不同的监管。致病表型，通常包括大量关键调节剂。因此，毒品和药物可以调节整个子网的组合是治疗最相关的干预并有更好的机会成功。在此应用中，我们建议开发新颖基于分子网络的药物重新定位方法，以识别单个FDA批准的药物以及它们的组合可能会逆转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包括小鼠大脑在内的多种模型系统中进行测试原代细胞，人IPSC衍生的脑细胞和AD小鼠模型。该项目将建立一个集成的平台完成了高度创新的系统和实验生物学成分，用于快速药物发现对于广告。