Project Grant R43AG078715

HIGH THROUGHPUT FUNCTIONAL SCREENING OF ANTI-SARCOPENIA THERAPEUTICS - SARCOPENIA IS A PROGRESSIVE AGE-RELATED LOSS OF SKELETAL MUSCLE MASS AND FUNCTION ASSOCIATED WITH AN INCREASED RISK OF FALLS, FRACTURES, DEPRESSION, MALNUTRITION, PROLONGED HOSPITAL STAYS, AND DEATH. THE ANNUAL HOSPITALIZATION COSTS OF THIS DISEASE IN THE US ALONE ARE $40.4 BILLION, ~4% OF THE TOTAL YEARLY EXPENDITURE, MAKING IT A SIGNIFICANT PUBLIC HEALTH BURDEN. YET, THERE ARE NO FDA-APPROVED TREATMENTS FOR SARCOPENIA. THE NEED TO USE AGED RODENTS OR THEIR TISSUES FOR COMPOUND SCREENS POSES A SUBSTANTIAL BARRIER TO DRUG DISCOVERY FOR THIS DISEASE. IN CONTRAST, THE NEMATODE CAENORHABDITIS ELEGANS PROVIDES A MORE AMENABLE MODEL SYSTEM FOR HIGH-THROUGHPUT ANTI- SARCOPENIA DRUG DISCOVERY. THE WORM SHOWS PROGRESSIVE LOSS OF MUSCLE STRUCTURE AND FUNCTION AS IT AGES, LEADING TO ANIMALS ENTERING A STATE OF DECREPITUDE CHARACTERIZED BY MINIMAL BODY MOVEMENT UNTIL THEY FINALLY DIE. PRELIMINARY DATA SHOWS THAT THE DECREPITUDE STATE STRONGLY CORRELATES WITH THE LOSS OF MUSCLE STRENGTH, PROVIDING AN ENDPOINT AMENABLE TO HIGH THROUGHPUT SCREENING. BUILDING ON THE PRELIMINARY DATA, THIS APPLICATION HAS TWO AIMS. IN AIM1, WE WILL DEVELOP A NEW HIGH-THROUGHPUT AI-ASSISTED WORKFLOW TO CLASSIFY ANIMALS INTO HEALTHY, DECREPIT, OR DEAD STATES. IMAGE LIBRARIES WILL BE ACQUIRED AND POSE-ESTIMATION ALGORITHMS WILL BE IMPLEMENTED TO DEVELOP A FAST METHODOLOGY TO QUANTIFY THE PERCENTAGE OF DECREPIT ANIMALS IN AN AGED POPULATION. IN AIM 2, WE WILL PERFORM A PRIMARY SCREEN WITH A LIBRARY OF COMPOUNDS KNOWN TO EXTEND LIFESPAN USING DECREPITUDE AND ANIMAL ACTIVITY AS ENDPOINTS. WE HYPOTHESIZE THAT SOME OF THE ANTI-AGING COMPOUNDS WILL ALSO IMPROVE HEALTHSPAN AND THEREFORE PROVIDE A NOVEL SOURCE OF THERAPEUTICS FOR SARCOPENIA. TO DIRECTLY VALIDATE THESE HITS, WE WILL MEASURE IMPROVEMENTS IN MUSCLE STRENGTH AND THE INTEGRITY OF SARCOMERES AND MITOCHONDRIA NETWORKS IN AGED ANIMALS. WE ANTICIPATE OUR SCREENING FRAMEWORK WILL BECOME THE BASIS FOR FUTURE SCREENING OF COMPOUND LIBRARIES FOR SARCOPENIA TREATMENT. IN ADDITION TO THE PROPOSED RESEARCH INVESTIGATIONS, THIS APPLICATION WILL LAY THE FOUNDATION FOR THE ENTREPRENEURIAL CAREER DEVELOPMENT OF THE PI. THE PI IS THE CO-INVENTOR OF THE TWO FOUNDATIONAL TECHNOLOGIES USED IN THE SCREENING PIPELINE AND HAS CO-FOUNDED A STARTUP COMPANY. THE PI AIMS TO TRANSITION INTO THE BUSINESS AND COMMERCIALIZE THE SCREENING TECHNOLOGIES. MENTORS WITH SIGNIFICANT BUSINESS EXPERTISE HAVE BEEN IDENTIFIED, AND ENGAGEMENT WITH THEM WILL ENABLE THE PI TO GROW IN HIS ROLE AS THE CHIEF TECHNOLOGY OFFICER. THE PI HAS DEVELOPED A CAREER DEVELOPMENT PLAN THAT AIMS TO BUILD EXPERTISE IN BUSINESS SKILLS, GEROSCIENCE RESEARCH, AND AI, WHICH IS SUPPORTED BY ENROLLMENT IN ONLINE COURSES AND ATTENDANCE AT PREMIER CONFERENCES IN THESE AREAS. A TEAM OF BUSINESS EXPERTS AND WORLD-CLASS ACADEMICIANS HAS BEEN ASSEMBLED TO MENTOR AND ANCHOR THE ENTREPRENEURIAL CAREER OF THE PI IN A STARTUP COMPANY THAT IS FOCUSED ON IMPROVING THE HEALTHSPAN OF THE ELDERLY.