HIGH THROUGHPUT OSTEOARTHRITIS DRUG SCREENING USING CLICK CHEMISTRY - PROJECT SUMMARY OSTEOARTHRITIS (OA) IS A DEGENERATIVE JOINT DISEASE. CARTILAGE DEGRADATION IS A HALLMARK OF OA ONSET, AND THE INHIBITION OF THIS PROCESS REPRESENTS AN EFFECTIVE THERAPEUTIC STRATEGY FOR OA TREATMENT. THERE IS A CRITICAL NEED TO IDENTIFY AND VERIFY DRUGS THAT CAN PREVENT OR DELAY THE ONSET OF CARTILAGE DEGRADATION AND OA PROGRESSION. THIS PROPOSAL AIMS TO REPURPOSE EXISTING FDA-APPROVED DRUGS FOR THE TREATMENT OF OA. SUCCESSFUL DRUG REPURPOSING REQUIRES THE ABILITY TO SCREEN LARGE LIBRARIES OF DRUGS EFFICIENTLY, BUT NO COMMONLY USED TECHNIQUES FOR EVALUATING CARTILAGE DEGRADATION ARE WELL-SUITED FOR HIGH-THROUGHPUT DRUG SCREENING. WE HAVE DEVELOPED A CLICK CHEMISTRY-BASED TECHNIQUE THAT ACCURATELY TRACKS CARTILAGE DEGRADATION IN RESPONSE TO INFLAMMATION. THIS STUDY WILL DEVELOP THE CLICK CHEMISTRY TECHNIQUE INTO A HIGH-THROUGHPUT DRUG SCREENING PLATFORM FOR OA TREATMENT. AIM 1 WILL USE THE PROPOSED HIGH-THROUGHPUT CLICK CHEMISTRY PLATFORM TO SCREEN 2,906 FDA-APPROVED DRUGS, IDENTIFYING CANDIDATES THAT CAN SUCCESSFULLY REDUCE INFLAMMATION-INDUCED CARTILAGE DEGRADATION. FROM THIS SCREENING, UP TO FIVE POTENTIAL HITS OR DRUG CANDIDATES WILL BE SELECTED FOR VALIDATION BASED ON CRITERIA INCLUDING FORMULATION, CLINICAL USE, ECONOMIC FEASIBILITY, SAFETY, PHARMACOKINETICS, AND BIOAVAILABILITY. AIM 2 WILL VERIFY THE FIVE DRUG CANDIDATES USING AN EXPANDED CLICK CHEMISTRY STUDY TO THOROUGHLY CHARACTERIZE THE DRUGS' EFFECTS ON HUMAN CARTILAGE. ADDITIONALLY, ONE DRUG CANDIDATE WILL UNDERGO FURTHER VALIDATION THROUGH TWO APPROACHES: (I) AN ACL TRANSECTION RAT OA MODEL TO ASSESS THE DRUGS' ABILITY TO PREVENT OR DELAY OA PROGRESSION AFTER ACL DAMAGE, AND (II) A RETROSPECTIVE POPULATION ANALYSIS OF THE DELAWARE POPULATION, INVESTIGATING WHETHER THE SELECTED DRUG IS ASSOCIATED WITH REDUCED OA OCCURRENCE AMONG USERS. BEYOND REPURPOSING EXISTING MEDICATIONS, THIS PROJECT ALSO FOCUSES ON ENHANCING ANNIE PORTER'S TRAINING ACROSS MULTIPLE DISCIPLINES, INCLUDING BIOSTATISTICS, ANIMAL STUDIES, COHORT STUDIES, AND CLINICAL RESEARCH. DURING THE FELLOWSHIP, ANNIE WILL UNDERGO COMPREHENSIVE TRAINING TO DIVERSIFY HER TECHNICAL SKILLSET, GAIN NEW CLINICAL EXPERIENCES, AND CONTINUE DEVELOPING HER COMMUNICATION, LEADERSHIP, AND MENTORING SKILLS. ANNIE WILL COMPLETE THIS PROJECT AT THE UNIVERSITY OF DELAWARE, A RECOGNIZED LEADER IN THE OSTEOARTHRITIS AND ORTHOPEDICS FIELDS AND HOME TO THE DELAWARE CENTER FOR MUSCULOSKELETAL RESEARCH. ANNIE'S TRAINING TEAM INCLUDES SPONSOR DR. LU (A BIOENGINEER SPECIALIZING IN OA), CO-SPONSOR DR. FOX (AN EXPERT IN CLICK CHEMISTRY), DR. AXE (AN ORTHOPEDIC SURGEON), AND DR. ZHANG (DIRECTOR OF BIOSTATISTICS AT CHRISTIANA CARE HEALTH SYSTEM IN DELAWARE). THE INSTITUTIONAL ENVIRONMENT AND INTERDISCIPLINARY MENTORING TEAM ANNIE HAS IDENTIFIED WILL PROVIDE EXCELLENT SUPPORT IN HER TRAINING TO BE A SUCCESSFUL INDEPENDENT SCIENTIST IN TRANSLATIONAL MUSCULOSKELETAL RESEARCH.