NATURAL HISTORY, SEARCH FOR A MARKER AND THERAPY

这个项目的目标是定义自然历史，确定一个 诊断标志物，了解神经元功能障碍的机制， 在疾病发展的早期应用特定的治疗方法， Rett综合征（RS）的神经系统状态。基于RS假设 是一种早期大脑发育障碍，AIM 1专注于识别 年轻患者和早期临床特征的描述。家族性 病例和他们的谱系将被记录下来，以寻找一个遗传学上的 异常目标1中确定的病例将成为所有人的重要资源 项目在目标2中，将通过经典的PCR方法寻找RS缺陷基因。 细胞遗传学方法，并通过代表性差异分析（RDA）。 Aim 2还将寻找蛋白质和表达基因， 在RS中下调，这可以作为一个分子指纹， 疾病目的3研究嗅觉感受神经元（ORN） 从RS女孩的嗅觉神经上皮活检中获得， 与来自正常和疾病对照的ORN相比。细胞培养方法 将提供直接进入RS神经元的早期过程中， 疾病，并允许研究神经元缺陷的演变， disorder.在目标4中，治疗干预将试图预防 谷氨酸NMDA和AMPA受体增加的破坏性后果 通过用受体拮抗剂的特异性处理诱导神经元损伤， 美沙芬和托吡酯。为了弥补 胆碱乙酰转移酶水平降低， 乙酰胆碱酯酶促剂-盐酸多奈哌齐-以改善 认知将受到考验。将通过以下方式监测治疗疗效： 临床和神经成像技术。仔细研究营养成分 状态，以及吞咽困难在生长障碍中的作用将在 治疗干预的光。生长因子或基因的应用 当在动物中确定疗效时，将考虑治疗 模型

The goal of this project is to define the natural history, identify a diagnostic marker, understand the mechanism of neuronal dysfunction, and apply specific therapies early in the evolution of the disease to improve neurological status in Rett syndrome (RS). Based on the postulate that RS is a disorder of early brain growth, AIM 1 focuses on the identification of younger patients and delineation of early clinical features. Familial cases and their pedigrees will be documented in search of a genetic abnormality. Cases identified in Aim 1 will be a vital resource for all projects. In Aim 2 gene(s) defective in RS will be sought by classical cytogenetic approaches, and by representational difference analysis (RDA). Aim 2 will also search for proteins, and expressed genes that have up- or down regulated in RS, which may serve as a molecular fingerprint for the disease. Aim 3 is designed to study olfactory receptor neurons (ORNs) obtained from biopsies of olfactory neuroepithelium in RS girls, and compared to ORNs from normal and disease controls. A cell culture approach will provide direct access to RS neurons early in the course of the disease, and permit study of the evolution of neuronal defects in this disorder. In Aim 4 therapeutic interventions will attempt to prevent the devastating consequences of increased glutamate NMDA, and AMPA receptor induced neuronal injury by specific treatments with receptor antagonists, dextromethorphan and topiramate. To compensate for the significant reductions in choline acetyltransferase levels, treatment with an acetylcholine esterase inhibitor-donepezil hydrochloride- to improve cognition will be tested. Efficacy of treatment will be monitored by clinical and neuroimaging techniques. Careful study of the nutritional status, and the role of dysphagia in growth failure will be examined in the light of therapeutic interventions. Use of growth factors or gene therapy will be considered when efficacy is established in the animal model.