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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

雪旺细胞伸展细胞膜，同心地多层包裹轴突节段形成髓磷脂脱髓鞘作用沿着神经纤维除去沿着的髓鞘段。这种病理发生在在一组患病率较高的神经系统疾病中：格林-巴利综合征，慢性炎性脱髓鞘性多发性神经病、多灶性运动神经病、遗传性易感性神经病压力性麻痹（HNPP）和多发性硬化。髓鞘可能异常发育（髓鞘形成障碍），遗传性神经系统疾病因此，如果可以鉴定分子靶标并且来修复髓磷脂受我们最近观察的启发，我们提出这项研究涉及髓鞘连接蛋白和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，过度活化的p21激活激酶-1（PAK 1）在清除肿瘤细胞中起着关键作用。成熟髓鞘中的髓鞘连接。这些连接是由蛋白质组成的，它们密封了细胞之间的小空间，髓鞘层去除髓鞘连接导致缺失的小鼠中髓鞘过度渗透 Pmp 22基因的两个拷贝之一（Pmp 22 +/-），HNPP的真实模型。移除连接是一个节段性脱髓鞘的早期上游事件。相反，我们最近观察到，雪旺氏细胞中的PAK 2（外周神经中PAK的另一个家族成员）导致严重的髓鞘形成障碍的病理变化类似于先天性髓鞘形成不足的患者，提示PAK 2在髓鞘发育中的关键功能。因此，PAK 1/PAK 2活化的相对水平可能对髓鞘的发育和维持产生不同的影响。在本研究中，我们将首先验证PAK 1过度活跃与髓鞘去除之间的因果关系在几种周围神经病变小鼠模型中，然后我们将研究PAK 2 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