Regulation of PMP22 Expression in Peripheral Nerve

描述（由申请人提供）：遗传性周围神经病（也称为遗传性运动感觉神经病，HMSN）是影响神经系统的最常见遗传性疾病之一。最温和形式的人类周围神经病，腓骨肌萎缩症（CMT），在受影响的个体中引起运动和感觉神经的进行性恶化、肌肉萎缩和慢性疼痛/疲劳。大多数遗传性外周髓鞘病是由一个关键的髓鞘基因，外周髓鞘蛋白22（PMP 22），这是分类为CMT 1A的重复。由于这种疾病是由基因剂量效应引起的，因此实现PMP 22表达的轻微（<2倍）降低将有效治疗这种遗传性髓鞘病。最近使用候选化合物降低PMP 22表达水平的原理验证研究在CMT 1A的啮齿动物模型中显示出有益效果。在这些候选化合物进入临床试验之前，全面了解它们的分子靶点以及它们如何影响PMP 22的调节至关重要。 我们最近对PMP 22调控的研究已经阐明了由雪旺细胞发育的两个主要调控因子Egr 2/Krox 20和Sox 10控制的新型调控元件，本提案的目标是通过使用基因组编辑来删除内源性PMP 22基因座中的这些元件来测试这些元件的功能。此外，我们将使用斑马鱼分析来阐明这些增强子的发育控制。该提案还将探索协作转录因子的功能，这些转录因子将髓鞘施万细胞中发现的PMP 22表达放大至高水平。最后，使用我们已经开发的机制分析，我们建议确定蛋白酶体抑制剂的分子靶点，这是CMT 1A的候选治疗，因为它们最近在药物筛选中被确定为降低PMP 22的表达水平。

DESCRIPTION (provided by applicant): Hereditary peripheral neuropathies (also known as hereditary motor sensory neuropathies, HMSN) are among the most common genetic diseases affecting the nervous system. The mildest form of human peripheral neuropathy, Charcot-Marie-Tooth (CMT) disease, causes progressive deterioration of both motor and sensory nerves, muscular atrophy, and chronic pain/fatigue in affected individuals. A majority of inherited peripheral myelinopathies are caused by duplication of a critical myelin gene, Peripheral Myelin Protein 22 (PMP22), which is classified as CMT1A. Since this disorder results from gene dosage effects, achieving a slight (<2-fold) reduction in PMP22 expression would effectively treat this inherited myelinopathy. Recent proof-of-principle studies using candidate compounds to reduce PMP22 expression levels have shown beneficial effects in rodent models of CMT1A. Before such candidate compounds enter clinical trials, it will be critical to achieve a comprehensive understanding of their molecular targets and how they impact PMP22 regulation. Our recent studies of PMP22 regulation have elucidated novel regulatory elements controlled by two major regulators of Schwann cell development-Egr2/Krox20 and Sox10-and the goal of this proposal is to test the function of these elements by using genome editing to delete them in the endogenous PMP22 locus. In addition, we will use zebrafish analysis to elucidate the developmental control of these enhancers. This proposal will also explore the function of cooperating transcription factors that amplify PMP22 expression to the high levels found in myelinating Schwann cells. Finally, using the mechanistic analysis that we have developed, we propose to identify the molecular targets of proteasome inhibitors, which are a candidate treatment for CMT1A as they have been recently identified in a drug screen to lower the expression level of PMP22.