Project Grant R35NS137478

CNS DEMYELINATION: INITIATION, PROTECTION, AND CORRECTION - PROJECT SUMMARY THE LOSS OF CNS MYELIN, WHICH IS PRODUCED AND MAINTAINED BY OLIGODENDROCYTES, IS A CRITICAL ASPECT OF A WIDE RANGE OF NEUROLOGICAL CONDITIONS AND RESULTS IN THE ALTERED ELECTROPHYSIOLOGY OF THE DAMAGED AXONAL UNIT. MOREOVER, THE RESULTING MYELIN DEBRIS IMPEDE INTRINSIC EFFORTS TO REMYELINATE THE DEMYELINATED AXONS, AND THESE DEBRIS, WHICH ARE ENGULFED BY MICROGLIA, ALSO ACTIVATE AN INNATE IMMUNE RESPONSE, LEADING TO FURTHER INFLAMMATORY CNS DAMAGE. THE STUDIES DESCRIBED IN THIS PROPOSAL ARE CENTERED ON THREE ASPECTS OF DEMYELINATION: ACTIVATION, THE PROCESS BY WHICH OLIGODENDROCYTES ARE DAMAGED; PROTECTION, THE EFFORT TO SHIELD OLIGODENDROCYTES FROM FACTORS THAT LEAD TO THEIR DYSFUNCTION AND/OR DEMISE; AND CORRECTION, THE PROCESS BY WHICH DEMYELINATED AXONS ARE REMYELINATED. THIS R35 PROPOSAL REPRESENTS A CONVERGENCE OF FOUR SEPARATE, NINDS-SUPPORTED, STUDIES CENTERED ON VARIOUS ASPECTS OF THE FUNCTION AND DYSFUNCTION OF OLIGODENDROCYTES. THIS UMBRELLA AWARD WILL ALLOW US TO FOCUS OUR ENERGY ON HOW OUR UNDERSTANDING OF OLIGODENDROCYTE BIOLOGY, GAINED THROUGH THESE AWARDS, CAN BE CHANNELED INTO A DEEPER UNDERSTANDING OF THE HARMFUL IMPACT OF DEMYELINATION ON THE CNS, AS WELL AS HOW THIS DAMAGE CAN BE REDUCED AND REPAIRED. THESE EFFORTS WILL BENEFIT FROM ACCESS TO THE INDUCIBLE, GENETIC, OLIGODENDROCYTE ABLATION MOUSE MODEL (DTA) THAT WE DEVELOPED. IN ADDITION TO PROVIDING A MODEL OF ACUTE OLIGODENDROCYTE LOSS AND DEMYELINATION FOLLOWED BY ROBUST REMYELINATION, DTA MICE DEVELOP A LATE-ONSET, AUTOIMMUNE DEMYELINATING STAGE THAT MIMICS VARIOUS ASPECTS OF PROGRESSIVE MULTIPLE SCLEROSIS. OLIGODENDROCYTE PROTECTION BY THE INTEGRATED STRESS RESPONSE (ISR) HAS BEEN A MAJOR THEME OF OUR RESEARCH EFFORTS FOR OVER TWO DECADES, AND WE WILL EXTEND THIS LINE OF RESEARCH IN THE PROPOSED STUDIES. MOREOVER, OUR FUNDED STUDIES HAVE UNCOVERED THE CRITICAL ROLE OF THE ZINC FINGER PROTEIN ZFP24, AS WELL AS THE REVERSIBLE METHYLATION OF MRNA, IN THE MOLECULAR CONTROL OF OLIGODENDROCYTE DEVELOPMENT AND FUNCTION. THESE INSIGHTS WILL BENEFIT OUR EFFORTS TO BETTER UNDERSTAND AND ENHANCE THE CNS REMYELINATION PROCESS. TOGETHER, OUR PLANNED STUDIES SHOULD SIGNIFICANTLY ADVANCE OUR UNDERSTANDING OF THE CAUSES AND CONSEQUENCES OF DEMYELINATION AND REMYELINATION, WHICH ARE OF CONSIDERABLE RELEVANCE TO A WIDE RANGE OF NEUROLOGICAL DISORDERS THAT RESULT IN DISRUPTED CNS MYELIN.