Role of SOCS 3 in regulating oligodendroglial phenotype in health and disease

神经细胞，称为少突胶质细胞，对炎性侮辱的反应决定了多发性硬化症(MS)等脱髓鞘疾病的严重程度。我们先前已经发现，在这种反应中的一个关键蛋白是细胞因子白血病抑制因子(LIF)，它通过激活这些细胞上表达的LIF受体，限制它们的死亡，减少对MS动物模型的临床影响。然而，LIF的治疗益处是不完整的，我们还不完全了解LIF发挥这些作用的机制。为了最大限度地发挥LIF的治疗潜力，我们需要了解LIF受体信号是如何在神经系统中调节的。细胞因子信号转导3(SOCS3)分子是一种重要的调节LIF和其他细胞因子在体内其他器官的活性的蛋白质。我们最近发现，在MS的动物模型中，SOCS3的表达增加，这表明它可能在这一背景下调节LIF的活性。我们计划调查这一规定的性质。SOCS3可能限制了LIF的疗效，但也可能限制了不受限制的LIF受体信号的有害作用。为了区分这些可能性，我们计划研究脱髓鞘疾病对动物的影响，在这些动物中，SOCS3在少突胶质细胞中要么缺失，要么过表达。通过这种方式，我们应该能够学习如何优化LIF对多发性硬化症和相关神经系统疾病的治疗潜力。

The response of nerve cells, known as oligodendrocytes, to an inflammatory insult dictates the severity of demyelinating diseases such as multiple sclerosis (MS). We have previously discovered that a key protein in this response is the cytokine leukaemia inhibitory factor (LIF) which, by activating the LIF receptor expressed on these cells, limits their death and reduces the clinical impact on animal models of MS. However, the therapeutic benefit of LIF is incomplete and we do not completely understand the mechanisms by which LIF exerts these effects. To maximise the treatment potential of LIF we need to understand how LIF receptor signaling is modulated in the nervous system. An important protein known to regulate the activity of LIF and of other cytokines in other organs of the body is the suppressor of cytokine signaling 3 (SOCS 3) molecule. We have recently shown that the expression of SOCS 3 is increased in an animal model of MS, indicating that it is likely to modulate the activity of LIF in this context. We plan to investigate the nature of this regulation. SOCS 3 might limit the efficacy of LIF but it could also limit the deleterious effect of unbridled LIF receptor signaling. To distinguish between these possibilities, we plan to study the impact of demyelinating disease in animals in which SOCS 3 is either deleted or overexpressed in oligodendrocytes. In this way, we should be able to learn how to optimise the therapeutic potential of LIF in MS and related nervous system diseases.