Myelin Junction Therapy in Peripheral Neuropathies

周围神经病的髓磷脂连接治疗

• 批准号: 10735282
• 负责人: JUN LI
• 金额: $ 39.82万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10735282
• 关键词: Action Potentials; Affect; Axon; Binding; Cell membrane; Cells; Characteristics; Chronic Inflammatory Demyelinating Polyneuropathy; Cyclic AMP; Data; Demyelinating Diseases; Demyelinations; Development; Disease; Event; Excision; Family member; Functional disorder; GTP-Binding Protein beta Subunits; GTP-Binding Proteins; Guillain Barré Syndrome; Hereditary neuropathy with liability to pressure palsies; High Prevalence; Hyperactivity; Inherited; Knock-out; Lead; Maintenance; Modeling; Molecular Target; Multifocal Motor Neuropathy; Multiple Sclerosis; Mus; Myelin; Myelinated nerve fiber; Nerve; Nerve Fibers; Neuroglia; PMP22 gene; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Peripheral Nerves; Peripheral Nervous System Diseases; Permeability; Phenotype; Phosphotransferases; Play; Polyneuropathy; Principal Investigator; Proteins; Regulation; Role; Schwann Cells; Second Messenger Systems; Surrogate Markers; Testing; cell type; dysmyelination; effective therapy; kinase inhibitor; molecular targeted therapies; mouse model; myelination; nervous system disorder; novel; p21 activated kinase; p21-activated kinase 1; prevent; protein complex; remyelination; repaired; seal; targeted treatment; therapy development

Schwann cell extends its cell membrane to wrap around segments of axon concentrically for multiple layers and forms the myelin. Demyelination removes segments of myelin along the nerve fibers. This pathology occurs in a group of neurological disorders with collectively high prevalence: Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, hereditary neuropathy with liability to pressure palsies (HNPP) and multiple sclerosis. Myelin may be abnormally developed (dysmyelination) in inherited neurological diseases. Therefore, it is highly desirable if molecular targets can be identified and manipulated to repair myelin. Motivated by our recent observations, we propose this study to deals with myelin junction proteins and p21 activated kinase (PAK)-related pathway that likely become the molecular target. Our studies have discovered that hyperactive p21-activated kinase-1 (PAK1) plays a key role in removal of myelin junctions in matured myelin. These junctions are made by proteins that seal the small spaces between layers of myelin. Removal of myelin junctions lead to excessively permeable myelin in a mouse with a deletion of one of two copies of Pmp22 genes (Pmp22+/-), an authentic model for HNPP. The junction removal is an early event upstream to the segmental demyelination. In contrast, we recently observed that deficiency of PAK2 (another family member of PAK in the peripheral nerves) in Schwann cells results in severe dysmyelination with pathological changes similar to that seen in patients with congenital hypomyelination, suggesting a critical function of PAK2 in myelin development. Thus, relative levels of PAK1/PAK2 activation may differentially affect myelin development and maintenance. In this study, we will first verify the causal relationship between hyperactive PAK1 and removal of myelin junctions / demyelination in several peripheral neuropathy mouse models. We will then examine how PAK2 regulates myelin development. Finally, we will test whether PAK can be targeted to treat other peripheral nerve diseases. 1

雪旺细胞延伸其细胞膜，将轴突同心包裹多层。 形成髓鞘。脱髓鞘可去除神经纤维上的髓鞘片段。这种病理发生在 在一组普遍患病率较高的神经疾病中：格林-巴利综合征，慢性 炎症性脱髓鞘多神经病、多灶性运动神经病、遗传性神经病 导致压力性瘫痪(HNPP)和多发性硬化症。髓鞘可能发育异常(髓鞘功能障碍) 遗传性神经疾病。因此，如果能够识别和识别分子靶标是非常可取的 被操纵来修复髓鞘。受我们最近观察到的启发，我们建议进行这项研究来处理髓鞘 连接蛋白和p21激活的激酶(PAK)相关通路可能成为分子靶点。 我们的研究发现，高活性的p21-激活的激酶-1(PAK1)在去除 成熟髓鞘中的髓鞘连接。这些连接是由蛋白质组成的，这些蛋白质封闭了 一层层的髓鞘。去除髓鞘连接会导致带有缺失的小鼠髓鞘过度通透性 PMP22基因的两个拷贝之一(PMP22+/-)，是HNPP的真实模型。删除结点是一种 早期事件上游至节段性脱髓鞘。相比之下，我们最近观察到， PAK2(周围神经中PAK的另一个家族成员)在雪旺细胞中的表达导致严重的 髓鞘异常症的病理改变与先天性髓鞘减退症患者相似， 提示PAK2在髓鞘发育中具有重要作用。因此，PAK1/PAK2激活的相对水平 可能对髓鞘的发育和维持产生不同的影响。 在这项研究中，我们将首先验证过度活跃的PAK1与髓鞘去除之间的因果关系 几种外周神经病小鼠模型中的连接/脱髓鞘。然后我们将研究PAK2如何 调节髓鞘发育。最后，我们将测试PAK是否可以靶向治疗其他周围神经 疾病。 1