PATHOGENESIS OF RETT SYNDROME

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 Rett综合征（RS）主要影响女孩，在大多数情况下与MeCP 2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总体假设， 在大脑快速生长期间，遗传缺陷破坏了神经元的成熟及其相互连接， 突触形成并被修剪。五个互动项目将测试这一假设，最终目标是 提供合理的治疗。项目I将确定疾病的自然史和生物学基础， 通过神经学、神经影像学和分子学方法测定表型变异性。NMDA治疗/ 谷氨酸盐通道阻滞剂将用于预防兴奋性毒性并提供神经保护。项目B将 通过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 测量作为年龄函数的vesamicol结合，并鉴定RS患者， 抗胆碱酯酶抑制剂。此外，氯胺酮诱导的谷氨酸受体阻断对多巴胺 释放将被调查。此外，磁共振波谱（MRS）将确定谷氨酸随年龄的变化， 谷氨酸拮抗剂治疗的有效性。最后，纵向体积MRI分析将评估年龄相关的 区域变化。项目II将利用培养的嗅觉受体神经元（ORN）作为神经元的模型， 参与RS，其中将研究MeCP 2中各种突变和治疗干预的影响。 项目III将继续对细胞核MeCP 2的最新观察，以表征MeCP 2的表达和亚细胞 在具有和不具有不同MeCP 2突变的RS患者的淋巴细胞和脑中的定位，以及相关的 动物模型将表征细胞和组织样品中的转录调节因子复合物。功能 还将研究RS患者和动物模型的淋巴细胞和脑中MeCP 2缺陷的后果。 由组蛋白乙酰化的模式描绘。项目IV将确定改变MeCP 2表达对 谷氨酸受体个体发育、皮质可塑性和MeCP 2表达改变对小脑发育的影响; 检查具有各种MeCP 2突变的小鼠的形态学、神经学和行为学差异。皮质作为 以及来自突变小鼠的小脑颗粒神经元也将被培养， 将被探索。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.