The regulation of myelination by the p75-NFkB pathway

描述(申请人提供)：髓鞘对于神经冲动的快速传导、保护轴突免受损伤剂的伤害、为神经元提供营养支持以及调节受损轴突再生的能力是必要的。因此，导致脱髓鞘的病理情况，如多发性硬化症、格林-巴利综合征或神经损伤，可能会给患者带来灾难性的后果。髓鞘是由周围神经系统中的雪旺细胞和中枢神经系统中的少突胶质细胞对尚未确定的轴突信号做出反应而产生的多层结构。我们的总体目标是阐明调节这种基本神经结构形成的机制。我们最近证实，髓鞘前雪旺细胞中转录因子NFkB的激活是其分化为髓鞘表型所必需的。雪旺细胞中NFkB的抑制或基因缺失阻止了髓鞘的形成。NFkB的上游激活物仍有待确定，但p75神经营养素受体可以激活该转录因子，最近被证明在髓鞘形成过程中具有重要作用。在周围神经系统的发育过程中，p75在髓鞘前雪旺细胞中高度表达，但随着髓鞘的形成而开始下降，在成熟的髓鞘胶质细胞中很难检测到。然而，p75也在有髓感觉神经元中表达，因此尚不清楚p75‘S的关键功能是在雪旺细胞、神经元中特异表达，还是在两者中都有表达。我们的总体假设是，p75介导的NFkB激活是雪旺细胞形成髓鞘所必需的。我们将使用转基因动物和体外培养雪旺细胞和感觉神经元的髓鞘系统来研究这一提议。我们的具体目标是：(1)明确NFkB的激活机制。(2)通过有条件的基因缺失，研究髓鞘形成所需的p75表达。(3)检测p75在髓鞘前雪旺细胞内源性NFkB活性中的作用。(4)通过基因芯片进行基因表达谱分析和对已鉴定为受转录因子调控的髓鞘基因启动子的分析，确定NFkB在雪旺细胞中的靶基因。

DESCRIPTION (provided by applicant): Myelin is necessary for the rapid conduction of nerve impulses, the protection of axons from damaging agents, providing trophic support to neurons and regulating the ability of injured axons to regenerate. Hence, pathological conditions that cause demyelination such as Multiple Sclerosis, Guillian Barre Syndrome or nerve injury can have disastrous consequences for the afflicted individuals. Myelin is multilamellar structure produced by Schwann cells in the peripheral nervous system and oligodendrocytes in the CNS in response to axonal signals that have yet to be defined. Our overall objective is to elucidate the mechanisms regulating the formation of this essential neural structure. We recently demonstrated that activation of the transcription factor NFkB in pre-myelinating Schwann cells is essential for their differentiation into a myelinating phenotype. Inhibition or genetic deletion of NFkB in Schwann cells prevented myelin formation. The up stream activator of NFkB remains to be determined; however, the p75 neurotrophin receptor, which can activate this transcription factor, was recently shown to have an essential role in the process of myelination. During the development of the peripheral nervous system, p75 is highly expressed in pre-myelinating Schwann cells, but begins to decline as myelin forms and is difficult to detect in the mature, myelinating glia. Nevertheless, p75 is also expressed in the sensory neurons that become myelinated, thus it is unclear whether p75's critical function is specifically in Schwann cells, neurons or both. It is our overall hypothesis that p75 mediated activation of NFkB is required for Schwann cells to form myelin. We will investigate this proposal using transgenic animals and an in vitro myelination system of Schwann cells and sensory neurons in co-culture. Our specific objectives are: (1) Define the mechanisms of NFkB activation. (2) Investigate where p75 expression is required in order for myelin to form by use of a conditional gene deletion. (3) Determine the contribution of p75 to the endogenous NFkB activity in pre-myelinating Schwann cells. (4) Define the target genes of NFkB in Schwann cells through gene profiling by microarray and the analysis of promoters of myelin genes we have already identified as regulated by the transcription factor.