Mechanisms that regulate oligodendrocyte survival and myelin formation are an intense focus of research into repair in the lesions of multiple sclerosis (MS). Demyelination and oligodendrocyte loss are pathological hallmarks of the disease, and although increased oligodendrocyte numbers and remyelination are frequently observed in early lesions, it is clear that remyelination gradually fails as MS progresses. Current treatments for MS aim to reduce the incidence and severity of new lesion formation and clinical relapses, but these approaches have, to date, demonstrated little beneficial effect on regeneration and remyelination. For this reason, myelin repair and neuroprotection remain major goals for MS research. Accumulating evidence suggests that mediators produced locally play an important role in determining the success or failure of repair MS plaques, and the keys to understanding remyelination may therefore lie in molecular study of the lesion environment. Reactive astrocytes represent the most abundant cellular component of the MS plaque, and have been implicated as regulators of CNS inflammation and regeneration. We have investigated potential links between astrocyte reactivity and lesion repair using microarray analysis of cytokine-treated human astrocytes, and this approach has identified interleukin-11 (IL-11) as an astrocyte- derived factor that regulates oligodendrocyte survival and maturation, and myelin formation. IL-11 is induced in human astrocyte cultures by treatment with cytokines known to be expressed in MS plaques. In MS tissue samples, IL-11 is expressed by reactive astrocytes, with expression particularly localized to the myelin- containing border of both active and silent lesions. Its receptor, IL-11R alpha, is expressed by oligodendrocytes. In human cultures in vitro, treatment with IL-11 results in a significant increase in oligodendrocyte number, and this is associated with enhanced oligodendrocyte survival and maturation. Importantly, we have also found that IL-11 treatment is associated with a significant increase in myelin formation in rodent CNS cocultures. In addition, preliminary data from our laboratory indicate that IL-11 is protective in an animal model of MS. In this application, we will test the hypothesis that cytokine-induced expression of IL-11 in the astrocyte promotes oligodendrocyte survival and maturation, and remyelination.
Three Specific Aims are proposed. In the first, we will define the effects of IL-11 on oligodendrocytes, and the signaling pathways involved. In the second, we will determine the mechanism underlying the effects of IL-11 on myelin formation. In the third Aim, we will test for an association between IL-11 expression and oligodendrocyte preservation and remyelination in MS lesions. The experiments proposed in this application complement and parallel ongoing work in our laboratory using animal models, and the long-term goal of this work will be to identify novel therapeutic avenues to potentiate oligodendrocyte protection and myelin repair in the MS lesion. Current treatments for multiple sclerosis (MS) aim to reduce the incidence and severity of new lesion formation and clinical relapses, but to date have demonstrated little beneficial effect in terms of promoting regeneration and remyelination. Using a functional genomics-based approach, we have identified the gp130 cytokine interleukin-11 (IL-11) as an astrocyte-derived factor that has supportive effects on oligodendrocytes, and in this proposal we will test the hypothesis that cytokine-induced astrocytic expression of IL-11 potentiates oligodendrocyte survival and maturation, and remyelination, in the MS lesion. The long-term goal of this work will be to identify novel therapeutic avenues for potentiating oligodendrocyte protection and myelin repair in the context of inflammatory CNS demyelinating disease, the significance of which relates to improving the remyelinating capacity of the MS lesion. ? ? ?
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