The regulation of myelination by the p75-NFkB pathway

描述（由申请人提供）：髓磷脂对于神经冲动的快速传导、保护轴突免受伤害、为神经元提供营养支持和调节受伤轴突的再生能力是必需的。因此，导致脱髓鞘的病理条件，如多发性硬化症、吉莲-巴雷综合征或神经损伤，对受折磨的人来说可能会带来灾难性的后果。髓磷脂是一种多层结构，由周围神经系统的雪旺细胞和中枢神经系统的少突胶质细胞响应轴突信号而产生。我们的总体目标是阐明调节这一重要神经结构形成的机制。我们最近证明，在髓鞘形成前的雪旺细胞中，转录因子NFkB的激活是其分化为髓鞘形成表型所必需的。雪旺细胞中NFkB的抑制或基因缺失可阻止髓磷脂的形成。NFkB的上游激活因子仍有待确定；然而，可以激活该转录因子的p75神经营养因子受体最近被证明在髓鞘形成过程中起重要作用。在周围神经系统的发育过程中，p75在髓鞘形成前的雪旺细胞中高度表达，但随着髓鞘的形成，p75开始下降，并且在成熟的髓鞘胶质细胞中难以检测到。然而，p75也在有髓鞘的感觉神经元中表达，因此尚不清楚p75的关键功能是特异性地存在于雪旺细胞、神经元还是两者中。我们的总体假设是，p75介导的NFkB激活是雪旺细胞形成髓磷脂所必需的。我们将利用转基因动物和雪旺细胞和感觉神经元的体外髓鞘形成系统共同培养来研究这一建议。我们的具体目标是：(1)定义NFkB激活的机制。(2)利用条件基因缺失研究髓磷脂形成需要p75表达的地方。(3)确定p75对成髓鞘前雪旺细胞内源性NFkB活性的贡献。(4)通过基因芯片分析确定雪旺细胞中NFkB的靶基因，并分析我们已经确定的受转录因子调控的髓磷脂基因启动子。

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.