CONDUCTION BLOCK IN HNPP

HNPP 中的导电块

• 批准号: 8361939
• 负责人: JUN LI
• 金额: $ 2.47万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8361939
• 关键词: 17p11.2; Action Potentials; Animal Model; Chromosome Deletion; Chronic Inflammatory Demyelinating Polyneuropathy; Demyelinating Diseases; Development; Failure; Funding; Genes; Grant; Guillain-Barré Syndrome; Image Analysis; Inherited; Knockout Mice; Mechanics; Molecular; Multiple Sclerosis; Mus; Myelin; National Center for Research Resources; Nerve; Neurologic; Paralysed; Pathogenesis; Patients; Peripheral Nerves; Peripheral Nervous System; Predisposing Factor; Principal Investigator; Recovery; Research; Research Infrastructure; Resources; Sensory; Signal Pathway; Signal Transduction; Source; Therapeutic; United States National Institutes of Health; Wild Type Mouse; axonal degeneration; base; constriction; cost; disability; hereditary neuropathy; inhibitor/antagonist; insight; interest; novel; p21 activated kinase; pressure

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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 传导阻滞（CB）是沿神经沿神经的动作电位传播的失败，在许多中枢和周围神经系统的脱髓鞘疾病中引起神经障碍，包括吉利素 - 巴里综合征，慢性炎性炎症性抑制性脱氧蛋白脱发性多发性神经病和多发性硬化症。与轴突变性不同，CB的残疾可能是可逆的，应该特别容易受到理性疗法的影响。然而，CB的分子基础尚不清楚。有趣的是，具有遗传性神经病的患者对压力麻痹责任（HNPP），这是一种遗传性疾病，含有PMP22基因的染色体17p11.2的杂合缺失，对周围神经的机械力异常敏感，并可能产生可逆性的局灶性损失和敏感性损失和敏感性。我们正在使用HNPP的正宗动物模型，PMP22杂合敲除小鼠（PMP22 +/-）研究CB。我们发现，与野生型小鼠相比，PMP22 +/-小鼠在机械上诱导的CB可以更快地诱导。我们已经确定了由旁丙诺拉曲霉（HNPP）的病理标志（过度髓磷脂折叠）所包围的频繁焦距轴突收缩。我们假设曲曲霉/轴突收缩易感PMP22缺乏神经，以发展机械诱导的Cb。此外，我们已经表明，PMP22缺乏小鼠中P21激活的激酶类型1（PAK1）基因的灭活会消除tomacula/axonal限制，这是一种新型的信号传导机制。我们有兴趣研究CB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。我们的目的是定义易感PMP22 +/-神经的细胞和分子因子，并为机械诱导的CB，并建立了在PMP22缺乏症中形成tomaculum/轴突收缩的分子信号传导途径。预计结果将加深我们对CB分子基础的理解，这可能会使许多脱髓鞘疾病对发病机理有所了解。