Astrocyte regulation of CNS remyelination

描述（由申请人提供）：调节少突胶质细胞存活和髓磷脂形成的机制是多发性硬化症（MS）病变修复研究的热点。脱髓鞘和少突胶质细胞丢失是该疾病的病理标志，尽管在早期病变中经常观察到少突胶质细胞数量增加和髓鞘再生，但很明显，随着MS的进展，髓鞘再生逐渐失败。目前治疗多发性硬化症的目的是降低新病变形成和临床复发的发生率和严重程度，但迄今为止，这些方法对再生和髓鞘再生的有益作用很小。因此，髓磷脂修复和神经保护仍然是MS研究的主要目标。越来越多的证据表明，局部产生的介质在决定MS斑块修复的成功或失败中起着重要作用，因此，理解髓鞘再生的关键可能在于对病变环境的分子研究。反应性星形胶质细胞是MS斑块中最丰富的细胞成分，是中枢神经系统炎症和再生的调节因子。我们利用细胞因子处理的人类星形胶质细胞的微阵列分析研究了星形胶质细胞反应性和损伤修复之间的潜在联系，这种方法已经确定白细胞介素-11 （IL-11）是星形胶质细胞衍生的因子，调节少突胶质细胞的存活和成熟，以及髓磷脂的形成。IL-11在人类星形胶质细胞培养中被已知在MS斑块中表达的细胞因子诱导。在MS组织样本中，IL-11是由反应性星形胶质细胞表达的，其表达特别局限于活性和沉默病变的含髓磷脂的边界。其受体IL-11R α由少突胶质细胞表达。在体外培养的人类中，用IL-11处理导致少突胶质细胞数量显著增加，这与少突胶质细胞存活和成熟的增强有关。重要的是，我们还发现IL-11处理与啮齿动物中枢神经系统共培养中髓磷脂形成的显着增加有关。此外，我们实验室的初步数据表明，IL-11在ms动物模型中具有保护作用。在本应用中，我们将验证细胞因子诱导的星形胶质细胞中IL-11的表达促进少突胶质细胞的存活、成熟和髓鞘再生的假设。提出了三个具体目标。首先，我们将定义IL-11对少突胶质细胞的影响，以及所涉及的信号通路。其次，我们将确定IL-11对髓磷脂形成影响的潜在机制。在第三个目标中，我们将测试IL-11表达与MS病变中少突胶质细胞保存和再髓鞘形成之间的关系。本申请中提出的实验与我们实验室正在进行的动物模型实验相补充和平行，这项工作的长期目标将是确定新的治疗途径，以增强MS病变中的少突胶质细胞保护和髓鞘修复。目前多发性硬化症（MS）的治疗旨在降低新病变形成和临床复发的发生率和严重程度，但迄今为止在促进再生和髓鞘再生方面收效甚微。使用基于功能基因组学的方法，我们已经确定了gp130细胞因子白介素-11 （IL-11）作为星形胶质细胞衍生的因子，对少突胶质细胞具有支持作用，在本提议中，我们将验证细胞因子诱导的IL-11星形胶质细胞表达增强MS病变中少突胶质细胞的存活和成熟以及髓鞘再生的假设。这项工作的长期目标将是在炎症性中枢神经系统脱髓鞘疾病的背景下，确定增强少突胶质细胞保护和髓鞘修复的新治疗途径，其意义与改善MS病变的再髓鞘再生能力有关。

DESCRIPTION (provided by applicant): 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.