ROLE OF EGR2 MUTATIONS IN PERIPHERAL MYELINOPATHIES

EGR2 突变在周围性髓鞘病中的作用

• 批准号: 6687716
• 负责人: JEFFREY D MILBRANDT
• 金额: $ 38.5万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-15 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6687716
• 关键词: Adenoviridae; Retroviridae; Schwann cells; cell differentiation; developmental genetics; developmental neurobiology; diabetic neuropathy; electron microscopy; gene induction /repression; gene mutation; genetically modified animals; immunocytochemistry; laboratory mouse; laboratory rat; microarray technology; myelinopathy; nerve injury; neurogenesis; neurogenetics; polymerase chain reaction; transcription factor

DESCRIPTION (From the Applicant's Abstract): Inherited neuropathies are among the most common human genetic diseases. These syndromes are characterized by severe motor and sensory deficits secondary to abnormal nerve myelination resulting in significant patient morbidity and mortality. The underlying genetic defects of these neuropathies occur primarily in genes encoding the myelin structural proteins MPZ, PMP-22 and connexin-32. Recently, however, mutations in the transcription factor Egr2 have also been associated with these syndromes. The connection between Egr2 and these syndromes was made after peripheral nerves in Egr2-deficient mice appeared poorly myelinated due to a Schwann cell differentiation arrest at the promyelinating stage. Together, these results strongly suggest that Egr2 is a crucial regulator of a differentiation program, which culminates in the myelinating Schwann cell phenotype. In this proposal, we outline experiments aimed at understanding the molecular mechanisms by which Egr2 regulates the myelination process. Gain-of-function experiments using adenovirus infection of Schwann cells will be utilized to perform Egr2 target gene profiling via microarray screening. Egr2 mutants associated with inherited neuropathies will be characterized in in vitro myelination assays and tested for their ability to activate expression of Egr2 target genes. In addition, one of the neuropathy-associated Egr2 mutations is located in the domain that interacts with the Nab proteins, modulators of Egr2 activity. We will therefore investigate the role of the Nab proteins in regulating myelination. The presence of mutations in the Nabl or Nab2 genes will be sought in patients with inherited neuropathy. Finally, gene targeting will be used to produce mice that harbor neuropathy-associated Egr2 mutations in order to create mouse models of these inherited neuropathies. The peripheral nervous system of these mice will be examined for deficits in Schwann cell differentiation and peripheral nerve myelination. The expression of Egr2-regulated genes will be examined in nerves of these mutant mice. These studies will provide new insight into how mutations in Egr2 lead to peripheral neuropathies, information that may lead to novel therapies for these diseases.

描述（摘自申请人的摘要）：遗传神经病是 最常见的人类遗传疾病。这些综合征的特征是 严重的运动和感觉缺陷继发于异常神经髓鞘 导致严重的患者发病率和死亡率。基础 这些神经病的遗传缺陷主要发生在编码的基因中 髓磷脂结构蛋白MPZ，PMP-22和连接蛋白32。但是，最近， 转录因子Egr2中的突变也与这些相关 综合征。 EGR2与这些综合征之间的联系是在 EGR2缺陷小鼠中的周围神经似乎由于骨而骨髓 Schwann细胞分化在寄宿生阶段的停滞。一起， 这些结果强烈表明EGR2是A的关键调节剂 分化程序，最终在骨髓的schwann细胞中 表型。在此提案中，我们概述了旨在理解的实验 EGR2调节髓鞘过程的分子机制。 使用雪旺细胞腺病毒感染的功能性实验将 可以通过微阵列筛选来执行EGR2靶基因分析。 与遗传神经病相关的EGR2突变体将在In In中进行表征 体外髓鞘化测定并测试了它们激活表达的能力 EGR2靶基因的。另外，与神经病相关的EGR2之一 突变位于与NAB蛋白相互作用的域中 EGR2活动的调节剂。因此，我们将研究NAB的作用 调节髓鞘的蛋白质。 NABL或 遗传神经病患者将寻求NAB2基因。最后，基因 靶向将用于产生具有神经病相关EGR2的小鼠 突变是为了创建这些遗传神经病的小鼠模型。这 这些小鼠的周围神经系统将检查是否缺陷 Schwann细胞分化和周围神经髓鞘。表达 将在这些突变小鼠的神经中检查EGR2调节的基因的。这些 研究将为EGR2中的突变如何导致周围性提供新的见解 神经病，可能导致这些疾病新疗法的信息。