The role of oligodendroglial differentiation inhibitors p57kip2 and GPR17 in the pathology of Multiple Sclerosis

少突胶质细胞分化抑制剂 p57kip2 和 GPR17 在多发性硬化症病理学中的作用

• 批准号: 242505530
• 负责人: Dr. David Kremer
• 金额: --
• 依托单位: Neurosciences
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/242505530?language=en
• 关键词: role; oligodendroglial; differentiation; inhibitors; p57kip2

Oligodendrocytes, the myelinating glial cells of the central nervous system (CNS) provide protection, stability and electrical insulation to the processes of CNS neurons, the so-called axons, by producing myelin sheaths. Under pathophysiological conditions as they occur in the inflammatory autoimmune CNS disease Multiple Sclerosis (MS) these structures are attacked by the immune system and ultimately disintegrate leading to severe clinical symptoms such as paraesthesia, paresis or ataxia. The progenitors of the oligodendrocytes, the oligodendroglial precursor cells (OPCs) which are dispersed throughout the entire adult brain, play an important role regarding myelin sheath and nerve fiber regeneration and thus for clinical functional recovery. However, the prerequisite for successful CNS repair is the differentiation of these cells into mature myelin-forming oligodendrocytes, a process which is often impeded by molecules that actively inhibit myelin formation. In myelin oligodendrocyte glycoprotein-experimental autoimmune encephalomyelitis (MOG-EAE), the rat MS model, the applicant could identify the p57kip2 gene as a potent myelinating glial cell differentiation inhibitor which actively prevents OPC differentiation. As this observation provides new perspectives for future therapeutic approaches to overcome the endogenous remyelination blockade seen in demyelinating diseases it is important to reveal to what extent p57kip2 is also present in the brain tissue of MS patients and whether it affects oligodendroglial differentiation and survival. Furthermore, as there are several other inhibitory factors such as the recently described G protein-coupled receptor GPR17 which was found to interfere with OPC differentiation via intracellular processes similar to the ones observed in p57kip2 signaling the applicant would like to study to which extent these two factors interact during CNS inflammation. It is important to elucidate if these two molecules might converge functionally or act synergistically in the inhibition of glial differentiation processes and repair activity in MS in order to identify new potential therapeutic avenues which prospectively could result in enhanced clinical treatment strategies.

少突胶质细胞是中枢神经系统（CNS）的髓鞘形成神经胶质细胞，通过产生髓鞘为CNS神经元的过程（所谓的轴突）提供保护、稳定性和电绝缘。在炎性自身免疫性CNS疾病多发性硬化（MS）中发生的病理生理条件下，这些结构受到免疫系统的攻击，并最终分解，导致严重的临床症状，如感觉异常、麻痹或共济失调。少突胶质细胞的祖细胞，即分散在整个成人脑中的少突胶质前体细胞（OPCs），在髓鞘和神经纤维再生方面发挥重要作用，从而用于临床功能恢复。然而，成功的CNS修复的先决条件是这些细胞分化成成熟的髓鞘形成少突胶质细胞，这一过程通常受到活性抑制髓鞘形成的分子的阻碍。在髓鞘少突胶质细胞糖蛋白-实验性自身免疫性脑脊髓炎（MOG-EAE）大鼠MS模型中，申请人可以鉴定p57 kip 2基因为有效的髓鞘形成神经胶质细胞分化抑制剂，其积极阻止OPC分化。由于这一观察结果为未来的治疗方法提供了新的视角，以克服脱髓鞘疾病中出现的内源性髓鞘再生阻滞，因此重要的是要揭示p57 kip 2在多大程度上也存在于MS患者的脑组织中，以及它是否影响少突胶质细胞的分化和存活。此外，由于存在几种其他抑制因子，例如最近描述的G蛋白偶联受体GPR 17，其被发现通过与在p57 kip 2信号传导中观察到的过程类似的细胞内过程干扰OPC分化，申请人希望研究这两种因子在CNS炎症期间相互作用的程度。重要的是要阐明这两种分子是否可能在功能上收敛或协同作用，抑制胶质细胞分化过程和修复活性的MS，以确定新的潜在的治疗途径，前瞻性地可能导致增强的临床治疗策略。