Although central nervous system (CNS) remyelination in multiple sclerosis (MS) is well documented, that its occurrence and extent are not more widespread has perplexed investigators for many years. It is now accepted that MS lesions contain appreciable numbers of premyelinating oligodendrocytes, indicating that the potential for remyelination is not limited by the loss of these cells. These data would suggest that interactions between oligodendrocytes and their surrounding environment may determine the success or failure of remyelination. ? ? Reactive astrocytes are a prominent pathological feature of MS, and have been shown to interact with nonmyelinating oligodendrocytes in lesions. We have explored links between astrocyte reactivity and lesion repair using primary cultures of human astrocytes, and have found that treatment of these cultures with TGFBeta1, a cytokine upregulated in MS lesions, induces expression of Jagged1, a ligand for the Jagged/Notch/Hes developmental signaling pathway. Activation of Notch signaling is considered to be one of the mechanisms used in the developing CNS to maintain migrating oligodendrocytes in an immature state. Within and around active MS plaques lacking remyelination, we have found that Jagged1 is expressed by hypertrophic astrocytes, while its receptor Notch 1 and the downstream effector Hes5 localize to cells with an immature oligodendrocyte phenotype, and TGFBeta1 is associated with perivascular extracellular matrix. In contrast, there is negligible Jagged1 expression in remyelinated lesions. In addition, we have found that culturing immature primary human oligodendrocytes on either Jagged1-transfected 3T3 cells or TGFBeta1-treated astrocytes leads to a significant reduction in process outgrowth from these cells. ? ? In this application, we will test the hypothesis that events triggered by TGFBeta1 in the astrocyte culminate in Notch-mediated inhibition of oligodendrocyte maturation.
Three specific aims are proposed. In the first specific aim, we will define the major signaling pathways used by TGFBeta1 to induce Jagged1 in primary human astrocytes. In the second specific aim, we will determine whether TGFBeta1-treated astrocytes inhibit oligodendrocyte maturation via Notch signaling. In the third specific aim, we will correlate expression of TGFBeta1, Jagged1, and downstream Notch effectors with multiple sclerosis lesion activity. The experiments proposed in this application complement and parallel ongoing work in our laboratory using animal models, and our long-term goal will be to identify novel therapeutic avenues designed to encourage remyelination in the multiple sclerosis lesion. ? ?
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