Axonal Injury in Demyelinating Disease

描述（由申请人提供）：显性遗传性脱髓鞘 神经病，被称为Charcot-Marie-Tooth病1型（CMTI），是 最常见的遗传性神经疾病CMTI是由一个基因突变引起的， 由髓鞘形成的许旺细胞表达的几种基因，包括 PMP22、MPZ和GJBJ。虽然脱髓鞘是第一个病理性的 因此，轴突丢失而不是脱髓鞘本身是导致神经纤维变性的主要原因。 神经系统残疾在这份补助金中，我们将评估 在脱髓鞘神经病中破坏轴突-雪旺细胞相互作用， 确定脱髓鞘和髓鞘再生是否重组轴突 （i）遗传性脱髓鞘性神经病的几种动物模型， 和（ii）急性脱髓鞘的动物模型（溶血素后 注射到坐骨神经中）。这样，我们就可以确定， 脱髓鞘的不同遗传原因在分子水平上具有相似的作用， 轴突膜的组织，以及分子的时间顺序， 节点，paranodes和paranodes的组件被分解， 脱髓鞘并在髓鞘再生期间重新组装。我们还将确定 脱髓鞘神经病的轴突缺失是否可以在两个方面得到改善， 方法-通过用Wids或转基因小鼠繁殖Mpz/Po-无效和Pmp 22-无效小鼠 胶质源性神经营养因子（GDNF）过表达的小鼠 肌肉.如果表达Wlds基因或GDNF转基因保留了轴突 Mpz/Po-null和Pmp22-null小鼠，这将提供以下概念的证据： 针对神经元而不是髓鞘形成的许旺细胞的疗法可以 遗传性脱髓鞘神经病的有效治疗。

DESCRIPTION (provided by applicant): Dominantly inherited demyelinating neuropathies, known as Charcot-Marie-Tooth disease type 1 (CMTI), are among the most common inherited neurological diseases. CMTI is caused by mutations in one of several genes that are expressed by myelinating Schwann cells, including PMP22, MPZ, and GJBJ. Although demyelination is the first pathological consequence, axonal loss rather than demyelination per se, is the main cause of neurologic disability. In this grant, we will evaluate the consequences of disrupted axon-Schwann cell interactions in demyelinating neuropathies, by determining whether demyelination and remyelination reorganize the axonal membrane in (i) several animal models of inherited demyelinating neuropathy, and in (ii) an animal model of acute demyelination (after lysolecithin injection into the sciatic nerve). In this way, we will determine whether different genetic causes of demyelination have similar effects on the molecular organization of axonal membranes, and the temporal order in which the molecular components of nodes, paranodes, and juxtaparanodes are disassembled by demyelination and reassembled during remyelination. We will also determine whether axonal loss in demyelinating neuropathies can be ameliorated in two ways-by breeding Mpz/Po-null and Pmp22-null mice with either Wids or transgenic mice in which glial-derived neurotrophic factor (GDNF) is overexpressed in muscle. If expressing the Wlds gene or the GDNF-transgene preserves axons Mpz/Po-null and Pmp22-null mice, this will provide proof of the concept that therapies directed at neurons rather than myelinating Schwann cells can be effective treatments for inherited demyelinating neuropathies.