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

SOCS 3 在调节健康和疾病中少突胶质细胞表型中的作用

• 批准号: nhmrc : 305519
• 负责人: Prof Helmut Butzkueven
• 金额: $ 27.95万
• 依托单位: The University of Melbourne
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2004
• 资助国家: 澳大利亚
• 起止时间: 2004-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/role-socs-3-health-disease/94873
• 关键词: Role; SOCS; regulating; oligodendroglial; phenotype

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.

称为少突胶质细胞的神经细胞对炎性损伤的反应决定了脱髓鞘疾病如多发性硬化症（MS）的严重程度。我们以前已经发现，在这种反应中的一个关键蛋白质是细胞因子白血病抑制因子（LIF），通过激活这些细胞上表达的LIF受体，限制它们的死亡，并减少对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受体信号传导在神经系统中是如何调节的。已知调节LIF和身体其它器官中其它细胞因子活性的重要蛋白质是细胞因子信号传导抑制因子3（SOCS 3）分子。我们最近已经表明，SOCS 3的表达在MS的动物模型中增加，表明它可能在这种情况下调节LIF的活性。我们计划调查这项规定的性质。SOCS 3可能限制LIF的功效，但它也可能限制不受约束的LIF受体信号传导的有害作用。为了区分这些可能性，我们计划研究在少突胶质细胞中SOCS 3缺失或过表达的动物中脱髓鞘疾病的影响。通过这种方式，我们应该能够了解如何优化LIF在MS和相关神经系统疾病中的治疗潜力。