Mechanisms of Erbin regulation of remyelination

Erbin调控髓鞘再生的机制

• 批准号: 8442521
• 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/8442521
• 关键词: Affect; Axon; Carpal Tunnel Syndrome; Cell Proliferation; Cell membrane; Demyelinating Diseases; Development; Diagnosis; Disease; Immune; 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; Time; Veterans; War; cell behavior; injured; insight; mutant; nerve injury; novel; public health relevance; receptor; remyelination; repaired; research study; sciatic nerve; 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. PUBLIC HEALTH RELEVANCE: This proposal is aimed at delineating the cellular and molecular mechanisms for Erbin to regulate remyelination. Successful completion of the proposed research could lead to elucidation of novel mechanisms in nerve regeneration after injury. Results may also contribute to a better understanding of peripheral neuropathies of war veterans and development of potential targets for therapy and diagnosis.

描述（由申请人提供）： 在周围神经系统中，许旺细胞（SC）延伸质膜突起以用髓鞘包裹轴突。髓鞘厚度和结间距是神经传导速度的重要决定因素，对于精确控制脉冲传导的时间至关重要。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。 髓鞘再形成或髓鞘修复对于髓鞘疾病的恢复至关重要。然而，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（NRG 1），这是已知的是在周围神经系统中的髓鞘发育的关键，也在神经损伤后的髓鞘再生中发挥重要作用。在初步结果中，我们发现Erbin（一种与NRG 1受体ErbB 2相互作用的蛋白质）突变小鼠在受损神经轴突的髓鞘再生中受损，并且功能恢复缓慢。此外，在ErbB 2升高之前，在损伤的坐骨神经中诱导Erbin表达。值得注意的是，这种增加在Erbin缺失小鼠中被阻断。这些结果将Erbin鉴定为髓鞘再生的新调节剂，并且与Erbin通过调节NRG 1/ErbB 2信号传导促进再生轴突髓鞘再生的假设一致。为了验证这一假设，我们将1）表征Erbin突变小鼠中的髓鞘再生和NRG 1信号传导，其中Erbin被PDZ结构域截短，因此不能与ErbB 2相互作用，以确定Erbin和ErbB 2之间的相互作用是否对髓鞘再生重要; 2）理解Erbin调节髓鞘再生的细胞机制;研究Erbin对ErbB 2稳定性的调控作用。 这些目标的成功完成将阐明神经修复过程中控制SC行为的新机制，并深入了解Erbin如何调节NRG 1信号传导。结果可能有助于更好地了解退伍军人的周围神经病，并开发潜在的治疗和诊断目标。 公共卫生相关性： 本研究旨在阐明Erbin调控髓鞘再生的细胞和分子机制。这项研究的成功完成可能会导致阐明损伤后神经再生的新机制。结果也可能有助于更好地了解周围神经病变的退伍军人和发展的潜在目标的治疗和诊断。