NATURAL HISTORY, SEARCH FOR A MARKER AND THERAPY

自然历史，寻找标记和疗法

• 批准号: 6347583
• 负责人: SAKKUBAI R NAIDU
• 金额: $ 34.46万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6347583
• 关键词: Rett syndrome; SDS polyacrylamide gel electrophoresis; acetylcholinesterase; apoptosis; biomarker; biopsy; brain disorder chemotherapy; cell line; cell type; cerebral degeneration; clinical trials; cognition; cytogenetics; developmental neurobiology; dextromethorphan; dietary supplements; electron microscopy; enzyme inhibitors; family genetics; female; fluorescent in situ hybridization; gel electrophoresis; genetic regulation; happy puppet syndrome; human subject; human therapy evaluation; immunocytochemistry; in situ hybridization; longitudinal human study; magnetic resonance imaging; neurogenesis; neurons; neuropsychological tests; northern blottings; nutrition related tag; olfactory nerve; oral mucosa; pathologic process; phenotype; protein sequence; questionnaires; representational difference analysis; swallowing; tissue /cell culture; western blottings

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.

该项目的目的是定义自然历史，确定 诊断标记，了解神经元功能障碍的机制，并了解 在疾病进化的早期应用特定疗法以改善 RETT综合征（RS）中的神经状态。基于RS的假设 AIM 1是早期大脑生长的疾病，专注于识别 年轻患者和早期临床特征的描述。家族 病例及其血统会记录以寻找遗传 紊乱 etc。 AIM 1中确定的案例将是所有人的重要资源 项目。在AIM 2中，RS中有缺陷的基因将由经典寻求 细胞遗传学方法和通过代表性差分分析（RDA）。 AIM 2还将搜索蛋白质，并表达具有UP或 向下调节Rs，可以用作分子指纹 疾病。 AIM 3旨在研究嗅觉受体神经元（ORNS） 从RS女孩的嗅觉神经上皮的活检中获得， 与正常和疾病控制的ORN相比。细胞培养方法 将在早期提供直接访问RS神经元 疾病，并允许研究神经元缺陷的进化 紊乱。在AIM 4治疗干预措施中将试图防止 增加谷氨酸NMDA和AMPA受体的毁灭性后果 通过受体拮抗剂的特定治疗诱导神经元损伤， 右美感和托吡酯。弥补有意义的 胆碱乙酰转移酶水平的降低，用 乙酰胆碱酯酶抑制剂 - 盐酸盐 - 改善 认知将进行测试。治疗功效将由 临床和神经影像学技术。仔细研究营养 地位，吞咽困难在生长失败中的作用将在 治疗干预措施的光。使用生长因子或基因 在动物中建立功效时，将考虑治疗 模型。