ID of Genes Responsible for X-Linked Mental Retardation

导致 X 连锁智力低下的基因 ID

• 批准号: 7120091
• 负责人: TAO WANG
• 金额: $ 13.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7120091
• 关键词: clinical research; fragile X syndromes; functional /structural genomics; gene mutation; genetic mapping; genotype; human genetic material tag; human subject; laboratory mouse; mental retardation; messenger RNA; microarray technology; northern blottings; patient oriented research; phenotype; polymerase chain reaction; sex linked trait

DESCRIPTION (provided by applicant): Mental retardation is the most common cause of handicap in children and young adults and accounts for 2-3% in the general population. X-linked mental retardation (XLMR) occurs in 1 in 600 males and is genetically heterogeneous. Among the estimated more than 150-200 responsible loci on the X chromosome, less than 40 genes have been cloned. Delineation of the molecular basis of XLMR will contribute to our understanding of human cognitive development, and will lead to development of strategies for clinical management of XLMR patients. The candidate is interested in the study of the molecular mechanism of XLMR, with a long-term career goal to become a successful clinician scientist. To accomplish this goal, he developed a comprehensive career development plan to be carried at the Johns Hopkins University. There are three key components to the research plan: (1) training in bioinformatics and genomic research; (2) training in the clinical evaluation and care for patients with mental retardation; and (3) training in the patient-oriented clinical investigation. The candidate will attend graduate courses and seminars on genome research and on principles of clinical investigation. He will receive mentored training in clinical evaluation and care for patients with mental retardation. He will be responsible for the development of a clinical research protocol for this project. In addition, the candidate will participate in the weekly Genetic Clinic at the Johns Hopkins Hospital and the Mental Retardation Clinic at the Kennedy Krieger Institute. He has developed a strategy of using human X chromosome-specific cDNA microarray to identify responsible genes. This approach is designed to detect mutations that result in a change in the abundance of mRNA due to mechanism such as promoter mutations, gene deletions, and nonsense or frameshift mutations associated with nonsense-mediated mRNA decay. Once a candidate gene is identified, Northern blot and real-time PCR will be used to verify mRNA reduction followed by mutation analysis in the proband. Additional in vitro and in vivo studies will then be carried out to delineate the molecular mechanism of XLMR for each identified gene. Through the combined laboratory research and clinical training, the candidate wishes to develop a solid knowledge base and gain precious experiences in research and clinical care for patients with mental retardation. This will be invaluable to the advancement of the candidate's career to become an independent physician scientist.

描述（由申请人提供）： 智力低下是儿童和青少年残疾的最常见原因，占总人口的 2-3%。 X 连锁智力低下 (XLMR) 的发生率是每 600 名男性中就有 1 人发生，并且具有遗传异质性。 在 X 染色体上估计超过 150-200 个负责基因座中，只有不到 40 个基因被克隆。 XLMR 分子基础的描述将有助于我们了解人类认知发展，并将导致制定 XLMR 患者的临床管理策略。 候选人对XLMR分子机制的研究感兴趣，长期职业目标是成为一名成功的临床科学家。 为了实现这一目标，他制定了一项全面的职业发展计划，并将在约翰·霍普金斯大学实施。 研究计划包括三个关键组成部分：（1）生物信息学和基因组研究培训； （二）精神障碍患者临床评估和护理培训； (3) 以患者为中心的临床研究培训。 候选人将参加有关基因组研究和临床研究原理的研究生课程和研讨会。 他将接受精神发育迟滞患者临床评估和护理方面的指导培训。 他将负责制定该项目的临床研究方案。 此外，候选人还将参加约翰·霍普金斯医院每周一次的基因诊所和肯尼迪克里格研究所的智力迟钝诊所。 他开发了一种利用人类 X 染色体特异性 cDNA 微阵列来识别相关基因的策略。 该方法旨在检测由于启动子突变、基因缺失以及与无义介导的 mRNA 衰变相关的无义或移码突变等机制而导致 mRNA 丰度变化的突变。 一旦确定了候选基因，将使用 Northern blot 和实时 PCR 来验证 mRNA 减少，然后对先证者进行突变分析。 然后将进行额外的体外和体内研究，以描述 XLMR 对于每个已识别基因的分子机制。 通过实验室研究和临床培训相结合，候选人希望在精神发育迟滞患者的研究和临床护理方面建立坚实的知识基础并获得宝贵的经验。 这对于候选人成为一名独立的医师科学家的职业生涯的发展是非常宝贵的。