PATHOGENESIS OF RETT SYNDROME

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 Rett综合征(RS)主要影响女孩，在大多数情况下与MeCP2基因突变有关。 RS的发病机制尚不清楚，但研究人员的研究支持了总体假设 当大脑快速生长时，遗传缺陷会扰乱神经元的成熟及其相互连接 突触被形成和修剪。五个互动项目将检验这一假设，最终目标是 提供合理的治疗。项目I将确定该病的自然病史和生物学基础 神经学、神经成像和分子方法的表型可变性。使用NMDA/进行治疗 谷氨酸通道阻滞剂将用于预防兴奋性毒性和提供神经保护。项目IB将 用单光子发射计算机断层扫描(SPECT)确定体内胆碱能系统的状态 测量维沙米考结合作为年龄的函数，并确定RS患者是否需要接受治疗 抗胆碱酯酶抑制剂。氯胺酮阻断谷氨酸受体对多巴胺的影响 将对释放进行调查。此外，磁共振波谱(MRS)将测定谷氨酸随年龄的变化，以及 谷氨酸拮抗剂治疗的疗效。最后，纵向容量磁共振分析将评估与年龄有关的 和地区性变化。项目二将利用培养的嗅觉感受器神经元(ON)作为神经元模型 参与RS，其中将研究MeCP2的各种突变的影响和治疗干预。 项目III将继续最近对核外MeCP2的观察，以表征MeCP2的表达和亚细胞 不同MeCP2基因突变的RS患者淋巴细胞和脑内的定位 动物模型。将对细胞和组织样本中的转录调节复合体进行表征。功能性 RS患者和动物模型中淋巴细胞和脑中MeCP2缺陷的后果也将是 由组蛋白乙酰化模式描述。项目IV将确定改变MeCP2表达对 谷氨酸受体个体发育、皮质可塑性以及MeCP2表达改变对小脑发育的影响； 检测具有不同MeCP2突变的小鼠的形态、神经和行为差异。皮质AS 以及突变小鼠小脑颗粒神经元的培养和恢复MeCP2功能的方法 将会被探索。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Rett syndrome (RS) predominantly affects girls, and is associated in most cases with mutations in the MeCP2 gene. Pathogenetic mechanisms of RS are unknown, but the investigators' studies support the overall hypothesis that the genetic defect disrupts maturation of neurons and their interconnections during rapid brain growth when synapses are formed and pruned. Five interactive projects will test this hypothesis with the ultimate goal of providing rational treatments. Project I will determine the natural history of the disease and biological basis for phenotypic variability by neurological, neuroimaging, and molecular approaches. Treatment with a NMDA/ glutamate channel blocker will be instituted to prevent excitotoxicity and provide neuroprotection. Project IB will establish the status of the cholinergic system in vivo by single photon emission computerized tomography (SPECT) measurement of vesamicol binding as a function of age, and identify RS patients for treatment with anticholinesterase inhibitors. Also, the effect of ketamine-induced blocking of glutamate receptors on dopamine release will be investigated. In addition, MR-spectroscopy (MRS) will determine changes in glutamate with age, and efficacy of therapy with glutamate antagonists. Finally, longitudinal volumetric MRI analyses will assess age-related and regional changes. Project II will utilize cultured olfactory receptor neurons (ORNs) as a model of neuronal involvement in RS, in which effects of various mutations in MeCP2 and therapeutic interventions will be studied. Project III will pursue recent observations of extranuclear MeCP2 to characterize MeCP2 expression and subcellular localization in lymphocytes and brain of RS patients with and without different MeCP2 mutations, and in related animal models. Transcriptional regulator complexes in cellular and tissue samples will be characterized. Functional consequences of MeCP2 deficit in lymphocytes and brain from RS patients and animal models will also be delineated by patterns of histone acetylation. Project IV will determine the effect of altered MeCP2 expression on glutamate receptor ontogeny, cortical plasticity, and effect of altered MeCP2 expression on cerebellar development; examine morphological, neurological, and behavioral differences in mice with various MeCP2 mutations. Cortical as well as cerebellar granule neurons from mutant mice will also be cultured and methods to restore MeCP2 function will be explored.