The role of ERK1/2 MAP kinase signaling in CNS myelination

 描述(申请人提供)：髓鞘是由少突胶质细胞突起同心包裹产生的，对于大脑和脊髓远端区域神经元之间的有效和及时通信至关重要。在发育过程中，少突胶质细胞根据目标轴突的直径调整单个髓鞘的厚度，以确保适当的神经元功能。在多发性硬化症(MS)等脱髓鞘疾病中，髓鞘形成的重要性变得显而易见，在这些疾病中，髓鞘修复的最终失败会导致轴突变性和随后的身体损伤。此外，在MS病程早期发生脱髓鞘和重新髓鞘形成后，髓鞘厚度与轴突直径的匹配无法潜在地损害功能，使轴突容易受损。少突胶质细胞如何为确定大小的轴突产生适当厚度的髓鞘尚不清楚。为了设计有效的治疗方法来增强MS患者的髓鞘修复，需要全面了解对中枢神经系统(CNS)髓鞘生成至关重要的分子和信号通路。最近，我们发现ERK1/2是进化上保守的信号通路的关键介质，在成年小鼠中枢神经系统发育过程中和脱髓鞘损伤后，ERK1/2对于髓鞘的扩张既是必要的也是充分的。基于这些发现，我们假设ERK1/2通过其在控制髓鞘生长中的少突胶质细胞特有的作用而对中枢神经系统的功能起关键的调节作用。这项拟议的研究将使用一系列具有ERK1/2功能遗传缺失或获得的转基因小鼠模型来确定ERK1/2介导的髓鞘厚度变化的功能后果。使用可诱导系统，其中ERK1/2在少突胶质细胞谱系的特定阶段被激活，将使我们能够在两种不同的脱髓鞘损伤模型中，在髓鞘修复期间何时何地激活ERK1/2是最有益的。最后，我们将测试重要的ERK1/2相互作用蛋白的作用，以阐明激活的ERK1/2对髓鞘生长至关重要的分子机制和下游靶点。明确ERK1/2在髓鞘扩张中的作用将为寻找新的治疗靶点以促进脱髓鞘疾病患者的髓鞘修复提供新的见解。

 DESCRIPTION (provided by applicant): Myelin, produced by the concentric wrapping of oligodendrocyte processes, is critical for the effective and timely communication between neurons in distant regions of the brain and spinal cord. During development, oligodendrocytes tailor the thickness of individual myelin sheaths to the diameter of their target axons to ensure appropriate neuronal function. The importance of myelination becomes obvious in demyelinating diseases such as multiple sclerosis (MS) where the eventual failure of myelin repair results in axonal degeneration and subsequent physical impairments. Furthermore, following episodes of demyelination and remyelination that occur early in the disease course of MS, the matching of myelin thickness to axon diameter fails potentially compromising function and leaving axons vulnerable to damage. How oligodendrocytes generate the appropriate thickness of myelin for an axon of defined size is unknown. A comprehensive understanding of the molecules and signaling pathways important for the generation of central nervous system (CNS) myelin is needed in order to design effective therapeutics tailored to enhance myelin repair in MS patients. Recently, we discovered that ERK1/2, key mediators of an evolutionarily conserved signaling pathway, are both necessary and sufficient for the expansion of the myelin sheath during development and following demyelinating injury in the adult mouse CNS. Based on these findings we hypothesize that ERK1/2 are critical regulators of CNS function through their oligodendrocyte-specific role in controlling myelin sheath growth. The proposed studies will use a series of transgenic mouse models with genetic loss or gain of ERK1/2 function to define the functional consequences of ERK1/2-mediated changes in myelin thickness. The use of an inducible system, where ERK1/2 is activated at specific stages of the oligodendrocyte-lineage, will allow us to tease apart both where and when activated ERK1/2 is most beneficial during myelin repair in two different models of demyelinating injury. Finally, we will test the role of important ERK1/2 interacting proteins to elucidate the molecular mechanisms and downstream targets of activated ERK1/2 important for myelin sheath growth. Defining the function of ERK1/2 in myelin sheath expansion will provide new insights to aid in the identification of novel therapeutic targets to promote myelin repair in patients with demyelinating diseases.