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

Schwann细胞扩展其细胞膜，以缠绕多层围绕轴突的段缠绕并形成髓鞘。脱髓鞘消除了沿神经纤维的髓磷脂片段。这种病理发生在一组统一患病率的神经系统疾病中：吉兰 - 巴里综合症，慢性炎症性脱髓鞘性多神经病，多灶性运动神经病，遗传神经病责任压力麻痹（HNPP）和多发性硬化症。髓磷脂可能异常发育遗传神经疾病。因此，如果可以识别分子靶标，并且操纵以修复髓磷脂。由于最近的观察，我们提出了这项研究来处理髓鞘连接蛋白和p21激活激酶（PAK）相关的途径可能成为分子靶标。我们的研究发现，多动P21激活的激酶-1（PAK1）在去除中起关键作用成熟的髓鞘中的髓鞘连接。这些连接是由密封在之间的小空间的蛋白质制成的髓鞘层。去除髓磷脂连接处导致鼠标中的髓磷脂过度渗透性 PMP22基因（PMP22 +/-）的两个副本之一，这是HNPP的真实模型。拆卸是一个节段脱髓鞘上游的早期事件。相比之下，我们最近观察到 schwann细胞中的pak2（外周神经中的另一家家庭成员）导致严重与先天性低司白电性患者相似的病理变化的常发肿瘤变化，提出PAK2在髓磷脂发育中的关键功能。因此，PAK1/PAK2激活的相对水平可能会差异地影响髓磷脂的发育和维护。在这项研究中，我们将首先验证过度活跃PAK1和去除髓磷脂之间的因果关系几个周围神经病小鼠模型中的连接 /脱髓鞘。然后，我们将研究PAK2 调节髓磷脂的发展。最后，我们将测试是否可以针对PAK来治疗其他外周神经疾病。 1