ROLE OF HYALURONAN IN INHIBITION OF REMYELINATION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们的初步数据支持这样的观点，即少突胶质细胞和星形胶质细胞的CD 44表达升高与慢性脱髓鞘病变中高分子量HA的积累有关，并且这种HA阻止被募集到这些病变的少突胶质细胞祖细胞成熟为髓鞘形成细胞，导致髓鞘再生失败。为了验证这些假设，我们进行了以下具体目标的研究：（1）表征胶质细胞局灶性CD 44过表达如何影响HA积累和髓鞘再生。使用神经胶质细胞特异性启动子和已建立的慢病毒系统，我们将测试局灶性、短暂性CD 44过表达如何影响成人白色物质中HA的积累和髓鞘再生。(2)确定HA在髓鞘再生失败中的作用。使用体外和体内测定，我们将测试HA积累或降解如何影响脱髓鞘或髓鞘再生。(3)确定HA对少突胶质细胞祖细胞成熟的作用是否依赖于CD 44或其他HA受体。使用体外试验和在CD 44-null小鼠中的体内研究的组合，我们将确定高MW HA抑制少突胶质细胞祖细胞成熟为髓鞘形成细胞的能力是否是CD 44依赖性的或独立的。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.