Genetic Control of Myelination by EGR2 and NAB proteins

EGR2 和 NAB 蛋白对髓鞘形成的遗传控制

• 批准号: 8063330
• 负责人: John P Svaren
• 金额: $ 0.89万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8063330
• 关键词: Address; Affect; Binding; Binding Proteins; Charcot-Marie-Tooth Disease; Chromatin Remodeling Factor; Collaborations; Complement; Complex; Data; Deacetylase; Development; Diabetic Neuropathies; Disease; Elements; Enzymes; Evaluation; Event; Foundations; Gene Expression Microarray Analysis; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Programming; Genetic Transcription; Goals; Hereditary Disease; Human; Human Genetics; Indium; Individual; Introns; Leprosy; Link; Lipids; Maintenance; Medical; Membrane Proteins; Motor; Multiple Sclerosis; Muscular Dystrophies; Mutate; Mutation; Myelin; Myelin Basic Proteins; Myelin P0 Protein; Myelin Sheath; Nerve Fibers; Neural Conduction; Neuropathy; Nucleosomes; Peripheral; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Process; Proteins; Publishing; Regulation; Regulatory Element; Repression; Research Personnel; Response Elements; Role; Schwann Cells; Signal Transduction; Sterols; Symptoms; Syndrome; Techniques; Testing; Therapeutic; Work; afferent nerve; base; chromatin remodeling; gene repression; in vivo; innovation; insight; mutant; myelination; myelinopathy; novel; programs; research study; transcription factor

DESCRIPTION (provided by applicant): Formation of the myelin sheath is critical for rapid conduction of nerve signals in motor and sensory nerves. The EGR2/Krox20 transcription factor is a master regulator of the myelination program in peripheral nerve, and human genetics studies have identified several independent EGR2 mutations associated with myelination disorders such as Charcot-Marie-Tooth (CMT) disease and Dejerine-Sottas Syndrome, which constitute one of the most common types of human genetic diseases. Although EGR2 expression correlates with induction of many myelin-associated genes, very few direct targets of EGR2 activity have been identified, and interactions with other myelin-specific transcription factors remain relatively obscure. Novel techniques outlined in this proposal will analyze interaction of EGR2 with other transcription factors during myelination in vivo to address the following specific aims: To determine if EGR2 interaction with a conserved intron-associated element regulates Myelin Protein Zero expression. Myelin Protein Zero (MPZ) is one of the most highly expressed myelin genes, and is commonly mutated in peripheral neuropathies. This proposal will probe the mechanism by which EGR2 activates a newly discovered control element in the MPZ gene, and will elucidate the mechanism by which dominant EGR2 mutants cause disease. To test the role of EGR2/SREBP synergy in regulating myelination. This aim will explore the scope and mechanism by which EGR2 collaborates with Sterol Response Element Binding Proteins (SREBPs) to activate genes required for the myelination program. . To test the role of CHD4 in regulation of EGR2 target genes by NAB proteins during peripheral nerve myelination. This aim will provide the first mechanistic analysis of NAB repression of EGR2 target genes by investigating the role of the NuRD chromatin remodeling complex. Deficiencies in formation of the myelin sheath around nerve fibers are a central cause of several important medical disorders, including many types of muscular dystrophy, diabetic neuropathy, multiple sclerosis, and leprosy. Formation and maintenance of lipid-rich myelin is a complex process, and this proposal is directed towards understanding genetic control of the myelination process in the peripheral nervous system. These experiments will provide novel insights that will be vital for development, evaluation, and implementation of novel therapies for these diseases. .

描述（由申请人提供）：髓鞘的形成对于运动和感觉神经中神经信号的快速传导至关重要。EGR 2/Krox 20转录因子是外周神经中髓鞘形成程序的主要调节因子，并且人类遗传学研究已经鉴定了与髓鞘形成障碍（例如Charcot-Marie-Tooth（CMT）疾病和Dejerine-Sottas综合征）相关的几种独立的EGR 2突变，其构成最常见类型的人类遗传疾病之一。虽然EGR 2表达与许多髓鞘相关基因的诱导相关，但很少有EGR 2活性的直接靶点被确定，并且与其他髓鞘特异性转录因子的相互作用仍然相对模糊。本提案中概述的新技术将分析体内髓鞘形成过程中EGR 2与其他转录因子的相互作用，以解决以下具体目标：确定EGR 2与保守内含子相关元件的相互作用是否调节髓鞘蛋白零的表达。髓鞘蛋白零（MPZ）是最高表达的髓鞘基因之一，并且通常在周围神经病中突变。该提案将探索EGR 2激活MPZ基因中新发现的控制元件的机制，并将阐明显性EGR 2突变体引起疾病的机制。测试EGR 2/SREBP协同作用在调节髓鞘形成中的作用。这个目标将探索EGR 2与固醇反应元件结合蛋白（SREBP）合作激活髓鞘形成程序所需基因的范围和机制。.检测CHD 4在外周神经髓鞘形成过程中通过NAB蛋白调节EGR 2靶基因中的作用。这一目标将通过研究NuRD染色质重塑复合物的作用，提供EGR 2靶基因的NAB抑制的第一个机制分析。神经纤维周围髓鞘的形成缺陷是几种重要医学疾病的主要原因，包括许多类型的肌营养不良症、糖尿病性神经病、多发性硬化症和麻风病。富含脂质的髓鞘的形成和维持是一个复杂的过程，该建议旨在了解周围神经系统髓鞘形成过程的遗传控制。这些实验将提供新的见解，这将是至关重要的开发，评估和实施这些疾病的新疗法。.