** AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** OSTEOARTHRITIS (OA) IS THE MOST COMMON CAUSE OF CHRONIC LAMENESS IN HORSES AND PLACES A SIGNIFICANT ECONOMIC AND WELFARE BURDEN ON THE EQUINE INDUSTRY DUE TO THE COST OF TREATMENT AND LOSS OF USE OF AFFECTED ANIMALS. POST-TRAUMATIC OSTEOARTHRITIS (PTOA) AFFECTS EQUINE ATHLETES ACROSS BREEDS AND DISCIPLINES AND CAN LEAD TO SHORTENED CAREERS AND REDUCED QUALITY OF LIFE. WHILE THE PRECISE RISK OF A HORSE DEVELOPING PTOA AFTER AN INJURY (EITHER A SINGLE EVENT OR REPETITIVE USE), DATA FROM HUMAN STUDIES SUGGESTS THAT IT MAY BE AS HIGH AS 50% EVEN WITH SURGICAL INTERVENTION. UNFORTUNATELY, PTOA IS USUALLY ONLY DIAGNOSED AFTER PERMANENT CARTILAGE DAMAGE HAS OCCURRED AND THERE ARE NO AVAILABLE TREATMENTS THAT CAN HALT OR REVERSE THE DISEASE. IDEALLY, TREATMENT FOR PTOA WOULD BE STARTED BEFORE IRREVERSIBLE JOINT DAMAGE HAS OCCURRED. HOWEVER, THE DEVELOPMENT OF EARLY DIAGNOSTIC TESTS AND NEW TREATMENTS FOR PTOA RELIES ON OUR UNDERSTANDING OF THE EARLIEST TRIGGERING FACTORS FOR THE DISEASE AND HOW IT PROGRESSES IN ITS EARLY STAGES. THE OBJECTIVE OF THIS STUDY IS TO IDENTIFY THESE EARLY TRIGGERING FACTORS BY MEASURING CHANGES IN GENE AND PROTEIN EXPRESSION IN A MODEL OF JOINT INJURY THAT IS SPECIFICALLY DESIGNED TO MIMIC NATURALLY OCCURRING DISEASE IN HORSES. A MAJOR BENEFIT OF THE FETLOCK CHIP MODEL THAT WE WILL USE IS THAT THE HORSES CAN BE EVALUATED AT MULTIPLE TIME POINTS DURING THE STUDY, PROVIDING A VIDEO OF DISEASE-RELATED CHANGES IN THE JOINTS RATHER THAN JUST A SNAPSHOT OF DISEASE. FURTHER, THIS MODEL DOES NOT REQUIRE SACRIFICING THE SUBJECTS, AND THEREFORE ALL OF THE MEASUREMENTS THAT WILL BE USED COULD BE APPLIED TO CLINICAL PATIENTS IN THE FUTURE.TWELVE HORSES WILL BE ENROLLED IN THE STUDY. EACH HORSE WILL HAVE A SMALL BONE CHIP CREATED ARTHROSCOPICALLY IN ONE FRONT FETLOCK (METACARPOPHALANGEAL) JOINT. THE OTHER FRONT FETLOCK WILL BE SURGICALLY EXPLORED BUT NO CHIP WILL BE MADE, SERVING AS A CONTROL AND ALLOWING US TO USE FEWER HORSES WHILE STILL OBTAINING GOOD DATA FOR COMPARISONS. A SMALL SAMPLE OF JOINT FLUID AND A SAMPLE OF THE TISSUE LINING THE JOINT WILL BE TAKEN AT THE TIME OF SURGERY FOR BASELINE MEASUREMENTS OF GENE AND PROTEIN EXPRESSION. AFTER SURGERY, THE HORSES WILL UNDERGO AN EXERCISE PROGRAM. WEEKLY LAMENESS EXAMS WILL BE PERFORMED, AND ADDITIONAL SAMPLES OF JOINT FLUID WILL BE COLLECTED EVERY 8 WEEKS. A SECOND-LOOK SURGERY WILL BE PERFORMED AT 16 WEEKS AFTER INJURY; THE JOINTS WILL BE PHOTOGRAPHED AND ANOTHER SAMPLE OF THE TISSUE LINING EACH JOINT WILL BE COLLECTED. THE HORSES WILL THEN UNDERGO ANOTHER PERIOD OF EXERCISE WITH CLINICAL EVALUATIONS AND JOINT FLUID COLLECTION. FINALLY, 32 WEEKS AFTER INJURY, A THIRD ARTHROSCOPIC SURGERY WILL BE PERFORMED AT WHICH POINT THE BONE CHIP WILL BE REMOVED. CHANGES IN GENE EXPRESSION (FROM THE TISSUE LINING THE JOINT COLLECTED AT EACH SURGERY) AND PROTEIN EXPRESSION (FROM THE JOINT FLUID) WILL BE EVALUATED OVER TIME WITHIN THE INJURED JOINTS AND WILL ALSO BE COMPARED BETWEEN THE INJURED AND,NON-INJURED JOINTS. WE WILL DETERMINE WHICH, IF ANY, GENE AND PROTEIN CHANGES PREDICT CLINICAL CHANGES SUCH AS LAMENESS OR JOINT SWELLING OVER THE COURSE OF THE STUDY.AT THE END OF THIS PROJECT, WE EXPECT TO HAVE IDENTIFIED SOME OF THE EARLIEST CHANGES IN GENE AND PROTEIN EXPRESSION AFTER A JOINT INJURY, WHICH WILL FILL A CRITICAL GAP IN OUR UNDERSTANDING OF HOW PTOA BEGINS IN EQUINE ATHLETES. IN ADDITION TO INSIGHTS ABOUT THE DISEASE, WE EXPECT TO IDENTIFY GENES AND PROTEINS THAT COULD SERVE AS TARGETS FOR THE DEVELOPMENT OF EARLY DIAGNOSTIC TESTS OR FOR NEW TREATMENTS. IN THE FUTURE, WE WILL VERIFY OUR RESULTS IN HORSES WITH NATURALLY OCCURRING PTOA AS WE MOVE TOWARDS CLINICAL APPLICATIONS OF THIS WORK.