Project Grant R03NS135339

GENERATION AND CHARACTERIZATION OF A CRE-LOX REGULATED TRANSGENIC ZEBRAFISH MODEL OF SBMA - SPINAL AND BULBAR MUSCULAR ATROPHY (SBMA OR KENNEDY'S DISEASE) IS A SLOWLY PROGRESSIVE, X-LINKED NEUROMUSCULAR DISEASE AFFECTING MEN. IT IS CAUSED BY THE EXPANSION OF A CAG REPEAT WITHIN THE ANDROGEN RECEPTOR (AR) GENE, ENCODING A GLUTAMINE TRACT IN THE PROTEIN. WITH NO CURE OR THERAPY, IDENTIFYING POTENTIAL THERAPEUTIC INTERVENTIONS FOR THIS PATIENT POPULATION IS PRESSING. WE AIM TO CREATE A CRE-INDUCIBLE, LOW COST, AND HIGH-THROUGHPUT MODEL OF SBMA USING ZEBRAFISH. DISCOVERIES MADE FROM ZEBRAFISH RESEARCH ARE HIGHLY TRANSLATABLE TO HUMANS SINCE ZEBRAFISH ARE VERTEBRATES WITH EXTENSIVE STRUCTURAL HOMOLOGY TO HUMAN NEUROANATOMY AND MUSCLE PHYSIOLOGY. MORE SPECIFICALLY FOR SBMA PATIENTS, ZEBRAFISH EXPRESS AN AR THAT IS HIGHLY HOMOLOGOUS IN STRUCTURE AND FUNCTION TO HUMAN AR. CRE-INDUCIBILITY OF THE HUMAN AR TRANSGENE WILL ENABLE THE PRODUCTION OF FOUNDER LINES THAT ARE ABLE TO EXPRESS HIGH LEVELS OF THE TOXIC POLYGLUTAMINE-EXPANDED AR. WE HYPOTHESIZE THIS WILL LEAD TO ROBUST MOTOR DYSFUNCTION IN LARVAL ZEBRAFISH. THESE LARVAL ZEBRAFISH MODELING SBMA WILL BE AMENABLE TO QUICK (OVER 1-2 WEEKS) CHEMICAL AND DRUG LIBRARY SCREENS, OR GENETIC MODIFICATION(S) TO IDENTIFY MODULATORS OF MOTOR FUNCTION. SUCH ASSAYS COULD BE SET UP WITHIN ONLY A FEW DAYS AND AT A VERY LOW COST COMPARED TO SUCH ASSAYS IN RODENT MODELS. MOREOVER, TISSUE SPECIFIC CRE ZEBRAFISH LINES CAN BE CROSSED WITH THESE SBMA ZEBRAFISH IN FUTURE STUDIES TO INVESTIGATE THE RELATIVE ROLE OF MOTOR NEURONS VERSES SKELETAL MUSCLE IN THE ONSET AND PROGRESSION OF SBMA PATHOGENESIS. A BETTER UNDERSTANDING OF THE RELATIVE ROLES OF EACH OF THESE CELL TYPES IN DISEASE WILL SUPPORT CLINICAL TRIAL DESIGN FOR SBMA PATIENTS. FURTHER, BECAUSE SBMA SHARES PROPERTIES WITH OTHER NEURODEGENERATIVE, NEUROMUSCULAR, AND POLYGLUTAMINE DISEASES, THERAPEUTIC TARGETS IDENTIFIED IN THE SBMA ZEBRAFISH MODEL MAY ALSO BE APPLICABLE TO SOME OF THESE OTHER DISORDERS.