Functional Link Between Innate Immunity, Oligodendrocyte Development, and Myelina

健康相关性：超过40万美国人患有多发性硬化症（MS）， 严重残疾最终影响到总MS人群的约85%。残疾 多发性硬化主要是由于脱髓鞘和轴突损伤。轴突损伤本身与 在急性脱髓鞘病变中发生显著的轴突横断的脱髓鞘， 逐渐的轴突缺失与慢性脱髓鞘有关。预防脱髓鞘 和增强髓鞘再生对于保持CNS完整性和促进 我们认为TLR 2-MyD 88通路是MS恢复的核心。 脱髓鞘和髓鞘再生失败的过程。我们的假设是， 先天性免疫细胞中TLR 2-MyD 88通路的激活导致炎性 破坏少突胶质细胞、髓鞘和轴突，而激活少突胶质细胞、髓鞘和轴突， 少突胶质细胞中的信号通路阻断了它们的正常成熟， 髓鞘再生 长期目标：我们的长期目标是确定MS的分子途径， 在损伤和修复过程中发挥重要作用，用作治疗靶点。在这 我们的目标是确定TLR 2-MyD 88通路在 引起脱髓鞘和轴突损伤，并通过抑制髓鞘再生， 体内和体外建模。 研究方法：在每个目标中，共同的目标是确定 MS模型系统中的TLR 2-MyD 88通路，使用脱髓鞘、少突胶质细胞 死亡、轴突损伤、神经元死亡、少突胶质细胞成熟和髓鞘再生， 终点。在aim 1中，铜腙介导的脱髓鞘被用于研究 TLR 2-MyDBB信号通路在脱髓鞘过程中的作用及其在 对这个过程的先天免疫。相关基因敲除小鼠用于建立 TLR 2和MyD 88的功能意义。脱髓鞘的定量评估， 将导致少突胶质细胞死亡、轴突损伤、神经元死亡和炎症。 在目标2中，我们将研究TLR 2-MyD 88通路对髓鞘再生的影响， 铜腙和溶血素模型。髓鞘再生的定量评估， 少突胶质细胞成熟、少突胶质细胞存活、神经元存活和轴突生长。 将形成完整性。

Health Relatedness: Over 400,000 Americans are afflicted with multiple sclerosis (MS), with severe disability ultimately affecting ~ 85% of the total MS population. Disability in MS is primarily due to demyelination and axonal injury. Axonal injury itself is tied to demyelination as significant axonal transection occurs in acute demyelinatng lesions, and gradual axonal loss is linked to chronic demyelination. Preventing demyelination and enhancing remyelination are essential to preserving CNS integrity and promoting recovery in MS. We propose that the TLR2-MyD88 pathway is central to both the process of demyelination and failure of remyelination in MS. Our hypothesis is that activation of the TLR2-MyD88 pathway in innate immune cells leads to inflammatory destruction of oligodendrocytes, myelin, and axons, whereas, activation of this same pathway in oligodendrocytes blocks their normal maturation thus preventing remyelination. Long-term goals: Our long-term goals are to define molecular pathways in MS, that play essential roles in the injury and repair process, for use as therapeutic targets. In this proposal our goal is to determine the importance of the TLR2-MyD88 pathway in causing demyelination and axonal injury, and in inhibiting remyelination, through in vivo and in vitro modeling. Research Approach: In each aim, the common goal is to determine the function of the TLR2-MyD88 pathway in MS model systems using demyelination, oligodendrocyte death, axonal injury, neuronal death, oligodendrocyte maturation and remyelination as end points. In aim 1 cuprizone mediated demyelination is used to study the impact of the TLR2-MyDBB pathway on the process of demyelination and the contribution in innate immunity to this process. Relevant knock-out mice are used to establish functional significance of TLR2 and MyD88. Quantitative assessments of demyelination, oligodendrocyte death, axonal injury, neuronal death, and inflammation will be made. In aim 2 we will study the impact of the TLR2-MyD88 pathway on remyelination using the cuprizone and lysolecithin models. Quantitative assessments of remyelination, oligodendrocyte maturation, oligodendrocyte survival, neuronal survival, and axonal integrity will be made.