Myelin Junction Therapy in Peripheral Neuropathies

周围神经病的髓磷脂连接治疗

基本信息

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
项目类别：
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

项目摘要

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，以同心方式包裹轴突片段，形成多层并形成髓磷脂。脱髓鞘会去除沿神经纤维的髓磷脂片段。这种病理发生一组总体发病率较高的神经系统疾病：慢性吉兰-巴利综合征炎性脱髓鞘性多发性神经病、多灶性运动神经病、遗传性神经病压力性麻痹（HNPP）和多发性硬化症。髓鞘质可能异常发育（髓鞘形成障碍）遗传性神经系统疾病。因此，如果能够识别分子靶标并操纵修复髓磷脂。受我们最近观察的启发，我们提出这项研究来处理髓磷脂连接蛋白和 p21 激活激酶 (PAK) 相关通路可能成为分子靶点。我们的研究发现，过度活跃的 p21 激活激酶 1 (PAK1) 在去除成熟髓磷脂中的髓磷脂连接。这些连接是由蛋白质形成的，这些蛋白质密封了之间的小空间髓磷脂层。髓磷脂连接的去除导致缺失小鼠髓磷脂的渗透性过大 Pmp22 基因的两个拷贝之一 (Pmp22+/-)，HNPP 的真实模型。结点去除是一个节段性脱髓鞘上游的早期事件。相比之下，我们最近观察到缺乏雪旺细胞中的 PAK2（周围神经中 PAK 的另一个家族成员）会导致严重的髓鞘形成障碍，其病理变化与先天性髓鞘形成不足患者相似，表明 PAK2 在髓磷脂发育中具有关键功能。因此，PAK1/PAK2 激活的相对水平可能会不同程度地影响髓磷脂的发育和维持。在本研究中，我们将首先验证PAK1过度活跃与髓磷脂去除之间的因果关系几种周围神经病小鼠模型中的连接/脱髓鞘。然后我们将研究 PAK2 如何调节髓磷脂的发育。最后我们会测试PAK是否可以靶向治疗其他周围神经疾病。 1