Project Grant R03OD038388

SYNERGIZING COMMON FUND DATA FROM MOTRPAC AND LINCS FOR THE DISCOVERY OF NOVEL EXERCISE MIMETIC DRUGS - PROJECT SUMMARY EXERCISE REPRESENTS ONE OF THE MOST POWERFUL AND BENEFICIAL INTERVENTIONS FOR HEALTH AND WELLNESS, THOUGH PATIENTS WITH AND WITHOUT CHRONIC DISEASE STRUGGLE TO EXERCISE ENOUGH TO GARNER ITS BENEFITS. ONE SOUGHT AFTER APPROACH TO OVERCOMING THESE CHALLENGES IS TO PROVIDE THE BENEFITS OF EXERCISE PHARMACOLOGICALLY, A SO-CALLED "EXERCISE-IN-A-PILL" SOLUTION. THIS INVOLVES IDENTIFYING BIOMOLECULAR MECHANISMS RESPONSIBLE FOR EXERCISE BENEFITS AND ENGAGING THEM PHARMACOLOGICALLY USING SMALL MOLECULE AGENTS. TO ACCELERATE DISCOVERY OF EXERCISE MIMETIC DRUGS, THIS PROJECT SYNERGIZES EXISTING DATA FROM TWO NATIONAL INSTITUTES OF HEALTH COMMON FUND PROJECTS. THE MOLECULAR TRANSDUCERS OF PHYSICAL ACTIVITY CONSORTIUM (MOTRPAC) PROVIDES A MAP OF THE BIOMOLECULAR RESPONSE TO EXERCISE, WHILE THE LIBRARY OF INTEGRATED NETWORK-BASED CELLULAR SIGNATURES (LINGS) PROGRAM PROVIDES A MAP OF THE BIOMOLECULAR RESPONSE TO SMALL MOLECULE EXPOSURE. THE INVESTIGATORS HYPOTHESIZE THAT BIOMOLECULAR EXERCISE PATHWAYS AND SMALL MOLECULE DRUG CANDIDATES FROM THESE TWO RESOURCES CAN BE MATCHED BY THEIR SHARED BIOMOLECULAR "SIGNATURES". THE MAPS ARE LINKED BY MATCHING EXERCISE-INDUCED CHANGES IN BIOMOLECULAR EXPRESSION (I.E., A GENE EXPRESSION "SIGNATURE" OF EXERCISE) FROM MOTRPAC TO SIMILAR EXPRESSION CHANGES INDUCED BY SMALL MOLECULES FOUND IN LINGS. BY LINKING THESE TWO DATA SETS, THE PROJECT WILL CREATE A DETAILED, BROWSABLE, AND INTERACTIVE RESOURCE FOR IDENTIFYING POTENTIAL EXERCISE MIMETICS. AIM 1 SEEKS TO IDENTIFY BIOMOLECULAR SIGNATURES OF EXERCISE TRAINING FROM MOTRPAC BY ANALYZING PUBLICLY RELEASED MULTI-OMIC RESPONSE DATA FROM MOTRPAC'S EXERCISE TRAINING STUDIES IN YOUNG ADULT RATS. SPECIFIC OBJECTIVES INCLUDE: 1) IDENTIFYING BIOMOLECULAR "SIGNATURES" THROUGH GENE SET ENRICHMENT ANALYSIS, NETWORK CLUSTERING, AND GENE REGULATORY NETWORKS; 2) EVALUATING THE VALIDITY AND RELIABILITY OF THESE SIGNATURES ACROSS TISSUES, SEXES, AND TIMEPOINTS IN THE RAT STUDY; AND 3) GENERATING AN ANNOTATED DATABASE OF SIGNATURES FOR ALIGNMENT WITH LINGS. AIM 2 INTEGRATES MOTRPAC AND LINGS BIOMOLECULAR SIGNATURES IN A CLOUD-BASED INFRASTRUCTURE THAT MATCHES MOTRPAC SIGNATURES WITH THOSE AVAILABLE FROM LINGS. THIS INFRASTRUCTURE WILL BE DESIGNED TO 1) ORGANIZE, BROWSE, AND FITER THE MOTRPAC SIGNATURES DATABASE; 2) QUERY EXISTING CLOUD-BASED APPLICATIONS DEVELOPED BY LINGS FOR ENGAGEMENT WITH THEIR LIBRARY OF DATA; AND 3) DELIVER THESE RESULTS IN A VISUALLY INFORMATIVE AND INTERACTIVE WEB APPLICATION TO MAXIMIZE THE USER'S ABILITY TO GAIN NOVEL INSIGHTS. FUTURE EFFORTS WILL EXPAND THE INFRASTRUCTURE BY ADDING NEW MOTRPAC DATA AND ANNOTATING EXERCISE SIGNATURES WITH KNOWLEDGE FROM OTHER COMMON FUND DATASETS. ADDITIONALLY, THE PROJECT AIMS TO LEVERAGE RESULTS TO IDENTIFY AND PRIORITIZE PATHWAYS RELATED TO INSULIN RESISTANCE AND OTHER DISEASES FOR EXPERIMENTATION IN MODEL SYSTEMS. THIS COMPREHENSIVE APPROACH SEEKS TO ACCELERATE THE IDENTIFICATION OF EXERCISE MIMETICS AND PROVIDE VALUABLE RESOURCES TO TRANSLATIONAL RESEARCHERS AND STAKEHOLDERS IN THE PHARMACEUTICAL PIPELINE.