Project Grant R21OD036471

ESTABLISHING ACOMYS AS A GENETIC PLATFORM FOR REGENERATION RESEARCH - PROJECT SUMMARY MANY OF THE MAJOR BIOLOGICAL DISCOVERIES OF THE 20TH CENTURY WERE MADE USING VERY FEW MODEL SPECIES. THEY WERE CHOSEN FOR HISTORICAL EXPERIMENTAL TRACTABILITY, RATHER THAN BIOLOGICAL ATTRIBUTES RELEVANT TO CRITICAL BIOLOGICAL QUESTIONS OR RELEVANCE TO PRESSING GLOBAL HEALTH ISSUES. YET THE ADVENT OF EFFICIENT SEQUENCING TECHNOLOGIES HAS MADE THE STUDY OF NEW ORGANISMS FEASIBLE. FOR EXAMPLE, THE STUDY OF CULTURED FIBROBLASTS FROM INCREDIBLY LARGE, LONG-LIVED AND CANCER FREE BOWHEAD WHALES HAS REVEALED EXTRAORDINARY ADAPTATIONS FOR EFFICIENT DNA REPAIR MECHANISMS IN THESE ANIMALS (1). YET BOWHEAD WHALES ARE NOT AT ALL EXPERIMENTALLY TRACTABLE OTHER THAN THROUGH CELL CULTURE. ACOMYS ARE AN EMERGING MODEL NON-FIBROTIC REGENERATION AND ARE THE ONLY KNOWN MAMMALIAN SPECIES WITH ANY SIGNIFICANT AND SYSTEMIC ADULT REGENERATIVE CAPACITY. AS A RODENT, ALBEIT WITH SOME UNUSUAL REPRODUCTIVE PHYSIOLOGY, THEY ARE READILY MAINTAINED IN THE LABORATORY, YET WE LACK TOOLS TO GENETICALLY EXPLOIT AND MANIPULATE THEIR NATURALLY SELECTED, ADVANTAGEOUS TRAITS. HISTORY HAS DEMONSTRATED THAT THE SUCCESS OF MODEL ORGANISMS IS SELF-PERPETUATING: AS THE COMMUNITY OF RESEARCHERS GROWS, NEW METHODOLOGIES AND RESOURCES ARE DEVELOPED AND SHARED, AND THE BODY OF SPECIFIC KNOWLEDGE AND ACCESS TO POWERFUL TOOLS TO MANIPULATE, OBSERVE AND EXPERIMENT UPON THESE MODEL ORGANISMS FURTHER LOWERS THE BAR TO ENTRY SO THAT THE CYCLE CAN REPEAT. HERE WE PROPOSE TO DEVELOP MULTIPLE GENETIC TOOLS INCLUDING INBRED LINES, ES CELLS FOR CHIMERIC AND ORGANOID ANALYSES, AND WHOLE ANIMAL TRANSGENESIS TO ESTABLISH ACOMYS AS EXPERIMENTALLY AND GENETICALLY TRACTABLE MODEL FOR MAMMALIAN NON-FIBROTIC REGENERATIVE HEALING AND HEALTHY AGING. THESE TECHNOLOGIES ARE FUNDAMENTAL TO DEFINE THE MECHANISMS DRIVING THE NATURALLY SELECTED REGENERATIVE CAPACITY IN THIS SPECIES, WHICH IN TURN ARE CERTAIN TO DRIVE THE CREATION OF NEW PRO-REGENERATIVE THERAPEUTICS FOR HUMAN REGENERATIVE MEDICINE.