Astrocyte regulation of CNS remyelination

描述(申请人提供)：调节少突胶质细胞存活和髓鞘形成的机制是多发性硬化症(MS)损伤修复研究的重点。脱髓鞘和少突胶质细胞丢失是该病的病理特征，尽管在早期病变中经常观察到少突胶质细胞数量增加和重新髓鞘形成，但很明显，随着MS的进展，重新髓鞘形成逐渐失效。目前治疗多发性硬化症的目的是减少新病变形成和临床复发的发生率和严重程度，但到目前为止，这些方法在再生和重新髓鞘形成方面几乎没有什么有益的效果。因此，髓鞘修复和神经保护仍然是多发性硬化症研究的主要目标。越来越多的证据表明，局部产生的介质在决定MS斑块修复成败中起着重要作用，因此了解再髓鞘形成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斑块中含量最丰富的细胞成分，被认为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脑星形胶质细胞的微阵列分析，研究了星形胶质细胞的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)是一种星形胶质细胞衍生因子，调节少突胶质细胞的存活和成熟以及髓鞘的形成。IL-11在人类星形胶质细胞培养中是通过用已知的在MS斑块中表达的细胞因子处理而诱导的。在MS组织样本中，IL-11由反应性星形胶质细胞表达，其表达尤其局限于活动期和静止期病变的含髓鞘边界。其受体IL-11Rα由少突胶质细胞表达。在体外培养的人类中，IL-11处理导致少突胶质细胞数量显著增加，这与促进少突胶质细胞的存活和成熟有关。重要的是，我们还发现IL-11治疗与啮齿动物中枢神经系统共培养中髓鞘形成的显著增加有关。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。在这一应用中，我们将检验细胞因子诱导的星形胶质细胞IL-11表达促进少突胶质细胞存活和成熟以及重新髓鞘形成的假设。提出了三个具体目标。首先，我们将确定IL-11对少突胶质细胞的影响，以及涉及的信号通路。在第二个实验中，我们将确定IL-11对髓鞘形成的潜在作用机制。在第三个目标中，我们将测试IL-11的表达与MS病变中少突胶质细胞的保存和重新髓鞘形成之间的关联。本申请中提出的实验是对我们实验室使用动物模型进行的工作的补充和平行进行的工作，这项工作的长期目标将是确定新的治疗途径，以加强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，但迄今在促进再生和重新髓鞘形成方面几乎没有显示出有益的效果。利用基于功能基因组学的方法，我们已经确定gp130细胞因子白细胞介素11(IL-11)是一种星形胶质细胞衍生的因子，对少突胶质细胞具有支持作用，在这项提议中，我们将检验细胞因子诱导的星形胶质细胞表达IL-11促进MS病变中少突胶质细胞的存活和成熟以及重新髓鞘形成的假设。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，确定加强少突胶质细胞保护和髓鞘修复的新的治疗途径，其意义与提高MS病变的重新髓鞘形成能力有关。

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.