Neuronal dysfunction in Rett Syndrome

雷特综合征的神经元功能障碍

• 批准号: 6753570
• 负责人: Joanna Molly Dragich
• 金额: $ 2.75万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6753570
• 关键词: CpG islands; DNA binding protein; PC12 cells; Rett syndrome; Xenopus; axon; dendrites; fluorescent in situ hybridization; gel mobility shift assay; gene expression; gene induction /repression; gene mutation; genetic markers; green fluorescent proteins; immunocytochemistry; injection /infusion; methylation; morphometry; nervous system disorder; neurogenesis; neurons; northern blottings; pathologic process; protein structure function; subtraction hybridization; western blottings

DESCRIPTION (provided by applicant): Mutations in the methyl CpG binding protein 2 (MeCP2) are the primary cause of the neurodevelopmental disorder, Rett syndrome (RTT). The current model predicts that MeCP2 functions in vivo to mediate transcriptional silencing by recruiting histone deacetylases to methylated cytosine residues throughout the genome. While the recent discovery of MeCP2 as the causative gene behind RTT provided a genetic marker to diagnosis the disorder, there is no link between the loss of function of MeCP2 and the etiology of RTT. The proposed studies will test the hypothesis that loss of function of MeCP2 will lead to the misexpression of genes that will ultimately cause neuronal dysfunction. Dysregulated genes will be identified from an immortalized neuronal cell line where MeCP2 activity has been disrupted. The loss of MeCP2 function in vitro and in vivo will be examined for involvement in neurite outgrowth and dendritic arborization. While commonly occurring mutations in MeCP2 will be studied to look at whether they display altered activity in the nucleus. The goal of the proposed study is to bridge the gap between our current understanding of the role of MeCP2 and of the underlying pathogenesis of RTT.

描述（由申请人提供）：甲基CPG结合中的突变 蛋白2（MECP2）是神经发育障碍的主要原因， RETT综合征（RTT）。当前模型预测MECP2在体内发挥作用 通过募集组蛋白脱乙酰基酶介导转录沉默 整个基因组中的甲基化胞嘧啶残基。而最近的发现 MECP2作为RTT背后的致病基因提供了遗传标记 诊断该疾病，MECP2功能丧失之间没有联系 和RTT的病因。拟议的研究将检验以下假设 MECP2功能的丧失将导致基因的misexpression 最终引起神经元功能障碍。将鉴定出失调的基因 从永生的神经元细胞系中，MECP2活性已经存在 破坏了。将检查MECP2功能在体外和体内的损失的损失。 参与神经突生长和树突状树皮化。虽然通常 将研究MECP2中发生的突变，以查看它们是否显示 细胞核中的活性改变。拟议的研究的目的是桥接 我们目前对MECP2和对的作用的理解之间的差距 RTT的潜在发病机理。