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。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子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沿着传播的失败，其导致中枢和外周神经系统的许多脱髓鞘疾病中的神经功能障碍，包括格林-巴利综合征、慢性炎性脱髓鞘性多发性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，并且应该特别容易受到合理治疗的影响。然而，CB的分子基础还不清楚。有趣的是，患有遗传性神经病易患压力麻痹（HNPP）的患者，一种含有PMP 22基因的染色体17p11.2杂合缺失的遗传性疾病，对周围神经上的机械力异常敏感，并发展可逆的局灶性无力和感觉丧失，这可能是由于CB。我们正在使用真实的HNPP动物模型，pmp 22杂合基因敲除小鼠（pmp 22 +/-）研究CB。我们发现，CB可以更迅速地机械诱导pmp 22 +/-小鼠比野生型小鼠。我们已经确定了频繁的局灶性轴突收缩包裹的结旁tomacula（过度的髓鞘折叠），一个病理标志的HNPP。我们推测，tomacula/轴突收缩倾向于PMP 22缺陷的神经发展机械诱导CB。此外，我们已经表明，PMP 22缺陷小鼠中p21激活激酶1型（pak 1）基因的失活消除了tomacula/轴突收缩，这是一种新的信号传导机制。我们有兴趣研究CB的发展和恢复的细胞和分子基础，tomacula/轴突收缩的形成，以及PAK抑制剂的治疗潜力。我们的目的是确定的细胞和分子因素，使pmp 22 +/-神经机械诱导CB，并建立在PMP 22缺陷的tomaculum/轴突收缩形成的分子信号通路。这些结果有望加深我们对CB的分子基础的理解，这可能有助于了解许多脱髓鞘疾病的发病机制。

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.