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)延伸质膜突起，用髓鞘包裹轴突。髓鞘厚度和节间距离是神经传导速度的重要决定因素，是精确控制定时冲动传导的关键。获得性髓鞘疾病包括神经损伤、腕管综合征、免疫介导的脱髓鞘疾病、多发性硬化症(MS)和格林-巴利综合征，其中一些已知会影响退伍军人。髓鞘再生或髓鞘修复对于髓鞘疾病的恢复至关重要。然而，人们对潜在的机制仍然知之甚少。最近的研究表明，神经调节蛋白1(NRG1)对周围神经系统髓鞘的发育至关重要，在神经损伤后的髓鞘再分化过程中也发挥着重要作用。在初步结果中，我们发现与NRG1受体ErbB2相互作用的Erbin突变小鼠损伤了受损神经轴突的重新髓鞘形成，功能恢复缓慢。此外，损伤坐骨神经中Erbin的表达先于ErbB2的表达。值得注意的是，这种增加在Erbin基因缺失的小鼠中被阻止。这些结果证实Erbin是一种新的再髓鞘形成调节因子，与Erbin通过调节NRG1/ErbB2信号来促进再生轴突再髓鞘形成的假设是一致的。为了验证这一假说，我们将1)鉴定Erbin突变小鼠的再髓鞘形成和NRG1信号，其中Erbin被PDZ结构域截断，从而无法与ErbB2相互作用，以确定Erbin和ErbB2之间的相互作用是否对再髓鞘形成至关重要；2)了解Erbin调控再髓鞘形成的细胞机制；以及3)研究Erbin如何调控ErbB2在干细胞中的稳定性和运输。这些目标的成功完成将阐明在神经修复过程中管理SC行为的新机制，并为Erbin如何调控NRG1信号提供洞察。研究结果可能有助于更好地了解退伍军人的周围神经疾病，并有助于开发潜在的治疗和诊断靶点。