Zhou Yadi, Fang Jiansong, Bekris Lynn M, Kim Young Heon, Pieper Andrew A, Leverenz James B, Cummings Jeffrey, Cheng Feixiong
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, 44195, USA.
Alzheimers Res Ther. 2021 Jan 13;13(1):24. doi: 10.1186/s13195-020-00760-w.
Recent DNA/RNA sequencing and other multi-omics technologies have advanced the understanding of the biology and pathophysiology of AD, yet there is still a lack of disease-modifying treatments for AD. A new approach to integration of the genome, transcriptome, proteome, and human interactome in the drug discovery and development process is essential for this endeavor.
In this study, we developed AlzGPS (Genome-wide Positioning Systems platform for Alzheimer's Drug Discovery, https://alzgps.lerner.ccf.org ), a comprehensive systems biology tool to enable searching, visualizing, and analyzing multi-omics, various types of heterogeneous biological networks, and clinical databases for target identification and development of effective prevention and treatment for AD.
Via AlzGPS: (1) we curated more than 100 AD multi-omics data sets capturing DNA, RNA, protein, and small molecule profiles underlying AD pathogenesis (e.g., early vs. late stage and tau or amyloid endophenotype); (2) we constructed endophenotype disease modules by incorporating multi-omics findings and human protein-protein interactome networks; (3) we provided possible treatment information from ~ 3000 FDA approved/investigational drugs for AD using state-of-the-art network proximity analyses; (4) we curated nearly 300 literature references for high-confidence drug candidates; (5) we included information from over 1000 AD clinical trials noting drug's mechanisms-of-action and primary drug targets, and linking them to our integrated multi-omics view for targets and network analysis results for the drugs; (6) we implemented a highly interactive web interface for database browsing and network visualization.
Network visualization enabled by AlzGPS includes brain-specific neighborhood networks for genes-of-interest, endophenotype disease module networks for omics-of-interest, and mechanism-of-action networks for drugs targeting disease modules. By virtue of combining systems pharmacology and network-based integrative analysis of multi-omics data, AlzGPS offers actionable systems biology tools for accelerating therapeutic development in AD.
近期的DNA/RNA测序及其他多组学技术推动了对阿尔茨海默病（AD）生物学和病理生理学的理解，但仍缺乏针对AD的疾病修饰治疗方法。在药物发现和开发过程中，将基因组、转录组、蛋白质组和人类相互作用组进行整合的新方法对于这一努力至关重要。
在本研究中，我们开发了AlzGPS（用于阿尔茨海默病药物发现的全基因组定位系统平台，https://alzgps.lerner.ccf.org ），这是一种综合的系统生物学工具，可用于搜索、可视化和分析多组学、各种类型的异质生物网络以及临床数据库，以识别靶点并开发针对AD的有效预防和治疗方法。
通过AlzGPS：（1）我们整理了100多个AD多组学数据集，这些数据集捕获了AD发病机制背后的DNA、RNA、蛋白质和小分子概况（例如，早期与晚期以及tau或淀粉样蛋白内表型）；（2）我们通过整合多组学研究结果和人类蛋白质 - 蛋白质相互作用网络构建了内表型疾病模块；（3）我们使用先进的网络邻近分析为约3000种FDA批准/研究中的AD药物提供了可能的治疗信息；（4）我们整理了近300篇关于高可信度药物候选物的文献参考；（5）我们纳入了来自1000多项AD临床试验的信息，记录了药物的作用机制和主要药物靶点，并将它们与我们针对靶点的综合多组学观点以及药物的网络分析结果相联系；（6）我们实现了一个高度交互式的网页界面，用于数据库浏览和网络可视化。
AlzGPS实现的网络可视化包括感兴趣基因的脑特异性邻域网络、感兴趣组学的内表型疾病模块网络以及针对疾病模块的药物作用机制网络。通过结合系统药理学和基于网络的多组学数据综合分析，AlzGPS提供了可操作的系统生物学工具，以加速AD治疗的开发。
