Regulation of PMP22 Expression in Peripheral Nerve

周围神经中 PMP22 表达的调节

基本信息

批准号：
8759907
负责人：
John P Svaren
金额：
$ 33.46万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8759907
关键词：
Affect Binding Binding Proteins Biological Assay Cell Differentiation process Charcot-Marie-Tooth Disease Chromosomes, Human, Pair 17 Clinical Trials Collaborations Deterioration Development Disease Down-Regulation Elements Enhancers Epigenetic Process Fatigue Foundations Gene Dosage Gene Expression Regulation Gene Targeting Genes Genetic Enhancer Element Genetic Transcription Genome Genomics Goals Hereditary Disease Hereditary Motor and Sensory Neuropathies Human Individual Inherited Lead Maps Mediating Molecular Target Motor Muscular Atrophy Mutation Myelin Myelin Proteins Nervous system structure Pathway interactions Pattern Peripheral Peripheral Nerves Peripheral Nervous System Diseases Physiological Play Positioning Attribute Preclinical Drug Evaluation Proteasome Inhibitor Regulation Regulatory Element Regulatory Pathway Rodent Model Role Schwann Cells Series Site Sterols Techniques Testing Transgenic Organisms Translating Translational Research Zebrafish afferent nerve base chromatin immunoprecipitation chronic pain design effective therapy experience in vivo multicatalytic endopeptidase complex myelination myelinopathy novel novel therapeutics public health relevance therapeutic target tool transcription factor

项目摘要

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.

描述（由申请人提供）：遗传周围神经病（也称为遗传性运动神经病，HMSN）是影响神经系统的最常见遗传疾病。人类周围神经病，charcot-marie-tooth（CMT）疾病的最温和形式导致运动神经和感觉神经，肌肉萎缩以及受影响个体的慢性疼痛/疲劳。大多数遗传性周围骨髓病是由临界髓磷脂基因，外周髓蛋白蛋白22（PMP22）的重复引起的，该基因被归类为CMT1A。由于这种疾病是由于基因剂量作用引起的，因此在PMP22表达中略有降低（<2倍）会有效地治疗这种遗传性骨髓病。使用候选化合物降低PMP22表达水平的最新原则研究表明，在CMT1A的啮齿动物模型中，有益作用。在此类候选化合物进入临床试验之前，要全面了解其分子靶标以及它们如何影响PMP22调节至关重要。我们最近对PMP22调控的研究阐明了由Schwann Cell Development-Egr2/Krox20和Sox10的两个主要调节剂控制的新型调节元件，该建议的目的是通过使用基因组编辑在内源性PMP22基因座中删除它们来测试这些元素的功能。此外，我们将使用斑马鱼分析来阐明这些增强剂的发展控制。该建议还将探索合作转录因子的功能，这些转录因子将PMP22表达扩增到髓鞘的Schwann细胞中的高水平。最后，使用我们开发的机械分析，我们建议识别蛋白酶体抑制剂的分子靶标，这是CMT1A的候选治疗方法，因为它们最近在药物筛选中被鉴定出来，以降低PMP22的表达水平。