Thursday, April 18, 2024
4/18/2024
Pathologically, multiple sclerosis (MS) can be identified by the presence of diffuse, discrete demyelinated areas, called plaques. Demyelination is a major feature of MS and therefore, an approach to the management of MS involves an increase in remyelination of axons, resulting in clinical improvement. Peroxisome proliferator-activated receptor ß or d (PPARß) being highly expressed in the CNS participates in many brain functions including myelination. Being a nuclear hormone receptor, PPARß needs ligand(s) for its activation and nuclear translocation. Therefore, identification of new nontoxic ligand of PPARß would be very important for promoting remyelination. The ß-hydroxy ß-methylbutyrate (HMB) is available in local GNC stores as a muscle-building supplement in human. It is a physiological molecule that is produced in human through the metabolism of L-leucine. HMB is known to increase exercise-induced gains in muscle size and muscle strength and improve exercise performance. Here, we will test an exciting hypothesis that HMB binds to the ligand-binding domain of PPARß (Specific aim I) and that HMB and its precursor L-leucine promote maturation of OPCs (Specific aim II) and stimulate remyelination in animal models (cuprizone and experimental autoimmune encephalomyelitis or EAE) of CNS demyelination (Specific aim III) via OPC-specific and/or microglia-specific PPARß. To investigate whether the muscle building effects of L-leucine and HMB could contribute to improved motor function in cuprizone and EAE models, Specific aim III will also examine the role of skeletal muscle-specific PPARß. A positive outcome of this cutting-edge R01 proposal will delineate easily available muscle-building supplement HMB as a physiological ligand of PPARß and enhance the possibility of promoting remyelination and treating patients with MS and other demyelinating disorders with HMB and its precursor L-leucine as primary or adjunct therapy.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
