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的遗传性疾病之一。最轻微的人类周围神经病变，Charcot-Marie-Tooth （CMT）病，会导致运动和感觉神经的进行性恶化，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一种关键髓鞘基因外周髓鞘蛋白22 （PMP22）的重复引起的，该基因被归类为CMT1A。由于这种疾病是由基因剂量效应引起的，因此实现PMP22表达的轻微（<2倍）减少将有效治疗这种遗传性脊髓病。最近使用候选化合物降低PMP22表达水平的原理证明研究在啮齿动物CMT1A模型中显示出有益的效果。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的调节将是至关重要的。我们最近对PMP22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egr2 /Krox20和sox10控制的新调控元件，本提案的目标是通过基因组编辑在内源性PMP22位点中删除这些元件来测试它们的功能。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。本研究还将探讨协同转录因子在髓鞘雪旺细胞中将PMP22的高水平表达放大的功能。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，蛋白酶体抑制剂是CMT1A的候选治疗方法，因为它们最近在药物筛选中被发现可以降低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.