Yadi Zhou1, Jiansong Fang1, Lynn M Bekris1,2, Young Heon Kim1, Andrew A Pieper3,4,5,6,7,8, James B Leverenz9, Jeffrey Cummings10,11, Feixiong Cheng12,13,14. 1. Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA. 2. Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, 44195, USA. 3. Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA. 4. Department of Psychiatry, Case Western Reserve University, Cleveland, OH, 44106, USA. 5. Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center, Cleveland, OH, 44106, USA. 6. Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA. 7. Weill Cornell Autism Research Program, Weill Cornell Medicine of Cornell University, New York, NY, 10065, USA. 8. Department of Neuroscience, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA. 9. Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH, 44195, USA. 10. Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, 89106, USA. 11. Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, UNLV, Las Vegas, NV, 89154, USA. 12. Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA. chengf@ccf.org. 13. Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, 44195, USA. chengf@ccf.org. 14. Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA. chengf@ccf.org.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Entities:
Keywords:
Alzheimer’s disease; Clinical trial; Drug repurposing; Genomics; Mechanism-of-action; Multi-omics; Network medicine; Systems pharmacology
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