ELUCIDATION OF DYSMYELINATION IN THE 18Q-SYNDROME

18Q 综合征中髓鞘形成异常的阐明

• 批准号: 6609659
• 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 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6609659
• 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（改编自申请人摘要）：中枢神经系统髓鞘形成障碍 神经系统是18 q综合征患者的一个关键特征， 染色体长臂缺失综合征 18号染色体。18 q患者的其他常见发现包括精神 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，研究人员已经确定， 这种综合征最常见的特征是髓鞘形成障碍。从分子 通过基因实验，他们已经确定了18号染色体上的一个区域， 在每一个髓鞘形成障碍的患者中缺失。因此，该地区是 “关键区域”的髓鞘形成障碍在这种综合征。 编码髓鞘碱性蛋白（MBP）的基因映射到这个关键的 染色体18 q上的区域。然而，小鼠模型已经证明， MBP基因的一个拷贝不足以引起脊髓中的髓鞘形成障碍。 老鼠.由于18 q综合征是一种邻接基因综合征，他们假设 在人类的这一区域中肯定有不止一个基因丢失 和小鼠的髓鞘形成障碍。因此，为了验证这一假设，他们建议 做一个小鼠模型，它缺少小鼠基因组的一个区域， 与他们在人体研究中发现的“关键区域”同源。 为了构建这种小鼠模型，他们提出了三个具体目标。第一个目标 是绘制他们在人类关键区域识别出的转录本 小鼠基因组中。第二个目标是开发一种小鼠模型， 使用Cre/loxP系统删除“关键区域”。第三个目标将 在这个小鼠模型中，用分子，结构， 和功能测定。 这些实验将帮助他们了解异常的机制。 18 q综合征患者的髓鞘形成。此外，该小鼠模型将 是未来研究的重要工具，重点是识别基因， 影响18 q综合征患者。这些研究的信息可以 最终导致对这种疾病的治疗干预。