Mechanisms of Erbin regulation of remyelination

Erbin调控髓鞘再生的机制

• 批准号: 9275337
• 负责人: Lin Mei
• 金额: --
• 依托单位: CHARLIE NORWOOD VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275337
• 关键词: Affect; Alpha Cell; Axon; Carpal Tunnel Syndrome; Cell Proliferation; Cell membrane; Demyelinating Diseases; Development; Diagnosis; Disease; ERBB2 gene; Immune; Impairment; Injury; Knockout Mice; Lead; Mediating; Molecular; Multiple Sclerosis; Mutant Strains Mice; Mutation; Myelin; Myelin Sheath; Natural regeneration; Nerve; Nerve Regeneration; Neural Conduction; Neuregulin 1; Peripheral Nervous System; Peripheral Nervous System Diseases; Play; Process; Proteins; Recovery; Recovery of Function; Regulation; Research; Role; Schwann Cells; Signal Transduction; Surface; Syndrome; Testing; Thick; Veterans; War; cell behavior; erbB-2 Receptor; experimental study; injured; insight; mutant; nerve injury; new therapeutic target; novel; remyelination; repaired; sciatic nerve; targeted treatment; trafficking

DESCRIPTION (provided by applicant): In the peripheral nervous system, Schwann cells (SCs) extend plasma membrane processes to wrap axons with myelin. Myelin sheath thickness and internodal distance are important determinants of nerve conduction velocity, which is critical for precise control of timing impulse conduction. Acquired myelin disorders include nerve injury, Carpal tunnel syndrome, immune-mediated demyelinating diseases, multiple sclerosis (MS) and Guillian-Barre syndrome, some of which are known to affect war veterans. Remyelination or myelin repair is critical for the recovery from myelin disorders. However, underlying mechanisms remain poorly understood. Recent studies demonstrate that neuregulin 1 (NRG1), which is known to be critical for myelin development in the peripheral nervous system, also plays an important role in remyelination after nerve injury. In Preliminary Results, we found that mutant mice of Erbin, a protein that interacts with the NRG1 receptor ErbB2, are impaired in remyelination of axons of injured nerves and slow in functional recovery. Moreover, Erbin expression was induced in injured sciatic nerves, in advance of elevation in ErbB2. Remarkably, this increase was blocked in Erbin null mice. These results identified Erbin as a novel regulator of remyelination and are in consistent with the hypothesis that Erbin promotes remyelination of regenerated axons by regulating NRG1/ErbB2 signaling. To test this hypothesis, we will 1) characterize remyelination and NRG1 signaling in Erbin mutant mice where Erbin is truncated with the PDZ domain and thus is unable to interact with ErbB2, to determine whether the interaction between Erbin and ErbB2 is important for remyelination; 2) to understand cellular mechanisms by which Erbin regulates remyelination; and 3) to investigate how Erbin regulates ErbB2 stability and trafficking in SCs. Successful completion of these aims will elucidate novel mechanisms that govern SC behavior during nerve repair and provide insight into how Erbin regulates NRG1 signaling. Results may contribute to a better understanding of peripheral neuropathies of war veterans and to development of potential targets for therapy and diagnosis.

描述（由申请人提供）： 在周围神经系统中，雪旺细胞（SCS）将质膜过程扩展到用髓磷脂包裹轴突。髓鞘鞘的厚度和损伤距离是神经传导速度的重要决定因素，这对于精确控制正时脉冲传导至关重要。获得的髓磷脂疾病包括神经损伤，腕管综合征，免疫介导的脱髓鞘疾病，多发性硬化症（MS）和吉利安 - 巴里综合症，其中一些众所周知会影响战争退伍军人。 透明度或髓磷脂修复对于从髓磷脂疾病中恢复至关重要。但是，潜在的机制仍然知之甚少。最近的研究表明，众所周知，神经蛋白1（NRG1）对于周围神经系统中的髓磷脂发育至关重要，在神经损伤后也起着重要作用。在初步结果中，我们发现，与NRG1受体ERBB2相互作用的Erbin的突变小鼠在对受伤神经的轴突的再髓膜中受损，功能恢复缓慢。此外，在ERBB2升高之前，在受伤的坐骨神经中诱导了Erbin的表达。值得注意的是，这种增加在Erbin Null小鼠中被阻止。这些结果将埃尔宾确定为新型的remereliation调节剂，并且与埃尔宾通过调节NRG1/ERBB2信号传导促进再生轴突的再生轴突的假设是一致的。为了检验该假设，我们将1）表征Erbin突变小鼠中Erbin与PDZ结构域截断，因此无法与ERBB2相互作用的Erbin突变小鼠中的Remereliation和NRG1信号传导，以确定Erbin和Erbb2之间的相互作用是否重要； 2）理解埃尔宾调节re髓的细胞机制； 3）调查Erbin如何调节SC中的ERBB2稳定性和贩运。 这些目标的成功完成将阐明在神经修复过程中控制SC行为的新型机制，并洞悉Erbin如何调节NRG1信号传导。结果可能有助于更好地理解战争退伍军人的周围神经病，并为治疗和诊断的潜在靶标发展。