Regulation of PMP22 Expression in Peripheral Nerve

描述(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的遗传性疾病之一。Charcot-Marie-Tooth(CMT)病是人类周围神经病中最轻微的一种，会导致运动神经和感觉神经进行性恶化，肌肉萎缩，以及患者的慢性疼痛/疲劳。大多数遗传性外周髓鞘病是由关键的髓鞘基因PMP22(PMP22)复制引起的，PMP22被归类为CMT1A。由于这种疾病是由基因剂量效应引起的，实现PMP22表达的轻微(2倍)减少将有效地治疗这种遗传性脊髓病变。最近使用候选化合物降低PMP22表达水平的原理验证研究表明，在CMT1A啮齿动物模型中有良好的效果。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PMP22调节将是至关重要的。我们最近对PMP22调控的研究阐明了由雪旺细胞发育的两个主要调控因子-Egr2/Krox20和Sox10-控制的新的调控元件，本提案的目标是通过使用基因组编辑来删除内源性PMP22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剂的发育控制。这项建议还将探索合作转录因子的功能，这些转录因子将PMP22的表达放大到髓鞘雪旺细胞中的高水平。最后，利用我们开发的机制分析，我们建议确定蛋白酶体抑制剂的分子靶点，这是CMT1A的候选治疗方法，因为最近在药物筛选中发现它们可以降低PMP22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.