This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.This project addresses the mechanisms by which the glycosaminoglycan hyaluronan (HA) accumulates in demyelinating lesions and whether it can influence the ability of oligodendrocyte progenitors to mature into myelin-forming cells in inflammatory demyelinating CNS lesions. Demyelination is the hallmark of numerous neurodegenerative conditions and is often linked to nervous system inflammation. Our preliminary data support the idea that elevated CD44 expression by oligodendrocytes and astrocytes is linked to the accumulation of high MW HA in chronic demyelinated lesions and that this HA prevents oligodendrocyte progenitors that are recruited to these lesions from maturing into myelin forming cells, resulting in remyelination failure. To test these hypotheses, we are conducting studies with the following specific aims: (1) To characterize how focal CD44 overexpression by glial cells influences HA accumulation and remyelination. Using glial cell-specific promoters and an established lentiviral system, we will test how focal, transient CD44 overexpression influences HA accumulation and remyelination in adult white matter. (2) To ascertain the contribution of HA to remyelination failure. Using in vitro and in vivo assays, we will test how HA accumulation or degradation influence demyelination or remyelination. (3) To determine if the effects of HA on oligodendrocyte progenitor maturation are dependent on CD44 or other HA receptors. Using a combination of in vitro assays and in vivo studies in CD44-null mice, we will determine if the ability of high MW HA to inhibit oligodendrocyte progenitor maturation to myelinating cells is CD44-dependent of independent.
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