Hsp70在多发性硬化症中联合纤粘连蛋白聚合体抑制髓鞘再生的研究

脱髓鞘是多发性硬化症的典型特征，髓鞘再生可减缓多发性硬化症病理进程。多种细胞外基质蛋白联合纤粘连蛋白聚合体长期存在，阻碍多发性硬化症病灶组织髓鞘再生。但纤粘连蛋白本身不能抑制髓鞘再生。因此，被聚合体联合的细胞外基质蛋白可能是阻碍髓鞘再生的主要靶标分子。然而，其中何种外基质蛋白抑制髓鞘再生的探究并未清晰。我们前期研究发现，细胞外基质蛋白Hsp70联合纤粘连蛋白聚合体诱导小胶质细胞/巨噬细胞形成不能支持髓鞘再生的细胞表型。因此，通过原代细胞培养、前脑组织培养、脱髓鞘的小鼠模型及多发性硬化症病灶组织，研究Hsp70是否抑制髓鞘再生以及确定其是否通过调控小胶质细胞/巨噬细胞，分泌OPCs分化成熟的抑制因子，从而抑制髓鞘再生。本研究的开展，有助于解除纤粘连蛋白聚合体对髓鞘再生抑制的研究，为解除纤粘连蛋白聚合体的抑制作用提供治愈靶标。

Multiple sclerosis (MS) is a chronic disabling central nervous system (CNS) disease, of which demyelination is one of major pathological feature. Myelin regeneration, i.e., remyelination, by oligodendrocyte progenitor cells (OPCs) prevents disease progression. Fibronectin aggregates (aFn) assemble several extracellular matrix (ECM) proteins to persistently exist in MS lesions, which impair remyelination. However, fibronectin per se hardly impedes remyelination. This indicates that assembled ECM proteins probably hinder remyelination. The purpose of this research is to clarify which assembled ECM protein possesses the ability to inhibit remyelination. Previously, our results show that aFn regulates phenotype of microglia/macrophages to impede OPCs differentiation. Similarly, Hsp70 modulates phenotype of microglia/macrophages. Therefore, in this research, primary glial cell culture, forebrain organotypic slice culture, induced demyelination animal model and MS lesions are used to study whether Hsp70 inhibits remyelination, and uncover the mechanism. In this manner molecules will be identified that can either modulate microglia/macrophages into remyelination-inhibiting phenotype or prevent OPCs differentiation and maturation, knowledge which is crucial in designing pharmacological strategies to manipulate the molecular microenvironment in the damaged nervous system to promote myelin repair in MS.