ELUCIDATION OF DYSMYELINATION IN THE 18Q-SYNDROME

18Q 综合征中髓鞘形成异常的阐明

• 批准号: 6540161
• 负责人: Robin Jean Leach
• 金额: $ 25.2万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 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 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6540161
• 关键词: disease /disorder model; gene deletion mutation; gene expression; genetic disorder; genetic mapping; laboratory mouse; model design /development; myelin basic proteins; myelinopathy; syndrome

DESCRIPTION (adapted from applicant's abstract): Dysmyelination of the central nervous system is a key feature in individuals with the 18q- syndrome, a syndrome that results from loss of chromosomal material from the long arm of chromosome 18. Other common findings in 18q- patients include mental retardation, developmental delay, and hearing impairment. Through the studies of over 40 patients with this syndrome, the investigators have established that the most common feature of this syndrome is dysmyelination. From molecular genetic experiments, they have identified a region on chromosome 18 that is missing in each patient with dysmyelination. This region is therefore the "critical region" for dysmyelination in this syndrome. The gene that codes for myelin basic protein (MBP) maps into this critical region on chromosome 18q. However, mouse models have demonstrated that loss of one copy of the MBP gene is not sufficient to cause dysmyelination in the mouse. Since the 18q- syndrome is a contiguous gene syndrome, they hypothesize that there is more than one gene that must be lost from this region in humans and mice to have dysmyelination. Thus to test this hypothesis, they propose to make a mouse model that is missing the region of the mouse genome that is homologous to the "critical region" they identified in their human studies. To construct this mouse model, they propose three specific aims. The first aim is to map the transcripts they have identified in the human critical region into the mouse genome. The second aim will be to develop a mouse model with a deletion of the "critical region" using the Cre/loxP system. The third aim will be to characterize the myelin in this mouse model using molecular, structural and functional assays. These experiments will help them gain insight into the mechanism of abnormal myelination in patients with 1 8qsyndrome. In addition, this mouse model will be an important tool for future studies that focus on identifying genes that affect patients with 18q- syndrome. The information from these studies could ultimately lead to therapeutic intervention for this disorder.

描述(摘自申请者的摘要)：中央型髓鞘障碍 神经系统是18q综合征患者的一个关键特征， 一种综合征，由长臂的染色体物质丢失引起 18号染色体。18Q患者的其他常见发现包括精神分裂症 发育迟缓、发育迟缓和听力障碍。通过研究 在40多名患有这种综合征的患者中，调查人员已经确定 这种综合征最常见的特征是髓鞘功能障碍。来自分子 基因实验，他们已经确定了18号染色体上的一个区域 在每一位髓鞘障碍患者身上都没有发现。因此，这一地区是 此综合征中髓鞘功能障碍的“临界区”。 编码髓鞘碱性蛋白(MBP)的基因映射到这个关键的 染色体18q上的区域。然而，小鼠模型已经证明了这种丢失 MBP基因的一个拷贝不足以导致髓鞘功能障碍 老鼠。由于18q综合征是一种相邻的基因综合征，他们假设 在人类的这个区域中，必须有不止一个基因丢失 和小鼠有髓鞘障碍。因此，为了检验这一假设，他们建议 制作一种缺失小鼠基因组区域的小鼠模型 与他们在人体研究中确定的“关键区域”同源。 为了构建这个小鼠模型，他们提出了三个具体目标。第一个目标 就是绘制出他们在人类关键区域识别的记录 进入老鼠的基因组。第二个目标将是开发一种具有 使用CRE/loxP系统删除“关键区域”。第三个目标将是 在这个小鼠模型中，用分子、结构来表征髓鞘 和功能分析。 这些实验将帮助他们深入了解异常的机制 18q综合征患者的髓鞘形成。此外，该鼠标模型将 是未来研究的重要工具，重点是识别 影响18q综合征患者。来自这些研究的信息可能 最终导致对这种疾病的治疗干预。