Axonal Injury in Demyelinating Disease

描述(申请人提供)：显性遗传性脱髓鞘 神经病，被称为夏科-玛丽-牙病1型(CMTI)，是 最常见的遗传性神经疾病。CMTI是由一种突变引起的 髓鞘雪旺细胞表达的几个基因，包括 PMP22、MPZ和GJBJ。尽管脱髓鞘是第一种病理性的 结果，轴突丢失而不是脱髓鞘本身是主要原因 神经性残疾。在这笔赠款中，我们将评估 脱髓鞘神经病中轴突-雪旺细胞相互作用的中断 确定脱髓鞘和重组髓鞘是否重组轴突 膜在(I)几种遗传性脱髓鞘神经病动物模型中， 和(Ii)急性脱髓鞘动物模型(在溶血磷脂之后 注射入坐骨神经)。通过这种方式，我们将确定是否 脱髓鞘的不同遗传原因对分子的影响相似。 轴突膜的组织，以及分子的时间顺序 节点组件、副节点组件和并列节点组件由 脱髓鞘并在重新髓鞘形成过程中重新组装。我们还将确定 脱髓鞘神经病的轴突丢失是否可以在两个方面得到改善 方法-通过用wids或转基因培育MPZ/Po缺失和PMP22缺失的小鼠 胶质源性神经营养因子(GDNF)高表达的小鼠 肌肉。如果表达Wlds基因或GDNF转基因可以保护轴突 MPZ/Po-Null和PMP22-Null小鼠，这将为 针对神经元而不是髓鞘雪旺细胞的治疗可以 对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.