CONDUCTION BLOCK IN HNPP

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 传导阻滞(CB)是一种动作电位沿神经传播的障碍，可导致许多中枢和外周神经系统脱髓鞘疾病的神经功能障碍，包括格林-巴利综合征、慢性炎症性脱髓鞘多神经病和多发性硬化症。与轴突变性的残疾不同，CB的残疾是可逆的，应该特别容易受到合理治疗的影响。然而，CB的分子基础还不是很清楚。有趣的是，遗传性压力性瘫痪(HNPP)是一种含有PMP22基因的染色体17p11.2杂合性缺失的遗传性疾病，患者对周围神经的机械作用力异常敏感，并出现可逆性局灶性无力和感觉丧失，这可能是由CB引起的。我们正在使用HNPP的真实动物模型-PMP22杂合基因敲除小鼠(PMP22/-)来研究CB。我们发现，在PMP22/-小鼠中，机械诱导CB的速度比野生型小鼠更快。我们发现HNPP的病理特征之一--结旁绒毛(髓鞘过度折叠)导致局灶性轴索收缩。我们假设绒毛/轴突收缩使PMP22缺陷神经易于发生机械性CB。此外，我们还发现，在PMP22缺陷的小鼠中，p21激活的激酶类型-1(PAK1)基因的失活可以消除绒毛/轴突收缩，这是一种新的信号机制。我们有兴趣研究CB发生和恢复的细胞和分子基础，绒毛/轴索收缩的形成，以及PAK抑制剂的治疗潜力。我们的目的是明确PMP22/-神经对机械诱导CB的易感性的细胞和分子因素，并为PMP22缺乏症的丘脑/轴索收缩的形成建立分子信号通路。这些结果有望加深我们对CB的分子基础的了解，这可能为许多脱髓鞘疾病的发病机制提供深入的认识。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Conduction block (CB), a failure of action potential propagation along the nerve, causes neurological disabilities in a number of demyelinating diseases of the central and peripheral nervous systems, including Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, and multiple sclerosis. Disabilities from CB can be reversible, unlike disabilities in axonal degeneration, and should be particularly susceptible to rational therapies. The molecular basis for CB, however, is not well understood. Interestingly, patients with hereditary neuropathy with liability to pressure palsies (HNPP), an inherited condition with heterozygous deletion of chromosome 17p11.2 containing the PMP22 gene, are abnormally sensitive to mechanical force on the peripheral nerve, and develop reversible focal weakness and sensory loss which are probably due to CB. We are studying CB using an authentic animal model of HNPP, the pmp22 heterozygous knockout mouse (pmp22+/-). We found that CB can be mechanically induced more rapidly in the pmp22+/- mice than that in wild-type mice. We have identified frequent focal axonal constrictions encased by paranodal tomacula (excessive myelin folding), a pathological hallmark of HNPP. We hypothesize that the tomacula/axonal constrictions predispose the PMP22 deficient nerves to develop mechanically induced CB. Moreover, we have shown that inactivation of the p21-activated kinase type-1 (pak1) gene in PMP22 deficient mice eliminates tomacula/axonal constrictions, a novel signaling mechanism. We are interested in investigating the cellular and molecular basis for the development and recovery of CB, the formation of tomacula/axonal constrictions, and the therapeutic potential of PAK inhibitors. We aim to define the cellular and molecular factors that predispose pmp22+/- nerves to mechanically induced CB, and establish molecular signaling pathway for the formation of tomaculum/axonal constriction in the PMP22 deficiency. Results are expected to deepen our understanding on the molecular basis of CB, which may render insights into the pathogenesis for many demyelinating diseases.