Remyelination by intranasal TIDM peptide

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Multiple sclerosis (MS) is the most common human demyelinating disorder of the central nervous system (CNS). Although the etiology of MS is unknown, it is connected to autoimmunity. At present, about 400,000 people in the United States have MS. It is more prevalent among Caucasians, particularly those of northern European ancestry, than others. Several evidences also show a potential link between the incidence of MS and combat service. For example, one study in the Annals of Neurology (2004, 55: 65-71) has identified 5,345 cases of MS among U.S. veterans that were considered "service-connected." Although the mechanism is not clear, viral infections, several vaccinations and/or exposure to different war zone chemicals may increase the risk of having MS. Accordingly, several veterans who served Gulf war 1 as well as many Vietnam veterans have been diagnosed with MS. Although there are some therapies against MS, no effective therapy is available to promote remyelination in MS. Therefore, delineation of new technologies for promoting remyelination is an important area of research. Oligodendrocytes (OLs) are the myelin-producing cells in the CNS and toll-like receptor 2 (TLR2) is an important member of innate immunity. It has been shown that TLR2 activation inhibits the maturation of oligodendroglial progenitor cells (OPCs). Since there was no specific inhibitor of TLR2, from structural analysis of the interaction between TLR2 and MyD88, the downstream partner of TLR2, we have designed a novel peptide corresponding to the TLR2-interacting domain of MyD88 (TIDM) that specifically blocks TLR2, but not other TLRs. Therefore, here, we want to test a translational, but novel, hypothesis that wtTIDM peptide stimulates the maturation of OPCs to OLs (Specific aim I) and that intranasal administration of wtTIDM peptide stimulates remyelination in animal models of demyelination (Specific aim II) via microglial and/or OPC TLR2 (Specific aim III). A positive outcome of this cutting-edge proposal will delineate if selective targeting of activated status of one component (TLR2) of the innate immune system by wtTIDM peptide increases the maturation of OPCs and stimulates remyelination, highlighting the discovery of a prospective intranasal agent to promote remyelination in MS and other demyelinating disorders.