Therapeutic Effects of Fibronectin Inhibitor Pur4 on Multiple Sclerosis in Mice

Multiple sclerosis (MS) is an autoimmune disease in the central nervous system (CNS) characterized by chronic inflammation, focal demyelination, and reactive glial scar formation. Neurological functional loss in MS is attributed to remyelination failure by oligodendrocytes followed by progressive axonal damage. Significant remodeling occurs in the extracellular matrix (ECM) in the CNS of chronic MS lesion, leading to the aberrant accumulation of ECM proteins. Recent studies have demonstrated that aggregated fibronectin (FN) assembled by astrocytes contributes to remyelination failure by impeding oligodendrocyte progenitor cell (OPC) recruitment and differentiation through b1 integrin-mediated signaling pathway. Thus, therapeutic strategies that target to the aberrant FN could be potentially used as a novel intervention for treating MS. pUR4, a recombinant peptide derived from F1 adhesin, is an effective inhibitor of FN deposition. Our recent work has indicated that pUR4 can decrease b1 integrin activation by depleting ECM FN. Our preliminary studies revealed that pUR4 decrease astrocyte activation and NF-kB-mediated signaling by depleting astrocyte-derived aberrant FN. These data suggest that pUR4 might promote OPC recruitment and differentiation, and attenuate astrocyte-induced neuroinflammation. Therefore, our global hypothesis in this proposal is that the FN inhibitor, reverses the inhibitory effects of aberrant FN fibrils on glial cells, and facilitates remyelination and the recovery of neuronal functions in MS. The specific aims to support our hypothesis are: 1) To determine whether pUR4 decreases cytokine-induced NF-kB activation, and downstream proinflammatory gene expression in reactive astrocytes through reducing b1 integrin activation. 2) To determine whether pUR4 overcomes the inhibiting effects of aberrant FN on OPC recruitment, differentiation and remyelination by decreasing b1 integrin-mediated PKC activation and/or actomyosin interaction. 3) To determine the therapeutic effects of pUR4 in an experimental autoimmune encephalomyelitis (EAE) model. These results will help us to explore the potential therapeutic effects of pUR4, and could lead to the development of a novel treatment strategy in the future.

Project ID:PC10907-1572
External Project ID:MOST109-2320-B182-019