AGE-RELATED NON-DISJUNCTION IN OOCYTES

卵母细胞中与年龄相关的不分离

• 批准号: 6363395
• 负责人: Patricia Hunt
• 金额: $ 30.73万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-05-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6363395
• 关键词: age at pregnancy; aging; aneuploidy; biological models; chromosome disorders; egg /ovum; female; human middle age (35-64); human subject; laboratory mouse; meiosis; nondisjunction; women's health

The likelihood of a chromosomally abnormal conception increases strikingly with age, and is a contributory factor in the age- related decrease in fertility in women. The consequences of these errors to human health are profound. The most common type of abnormality, aneuploidy, is the leading cause of mental retardation and pregnancy failure in our species. The basis of the age effect remains unknown, but recent molecular studies indicate that meiosis I (MI, the time at which homologous chromosomes segregate) is a critical time point in the genesis of most meiotic errors. In this proposal we outline direct studies of human oocytes to examine the mechanism of non-disjunction and the age association for individual human chromosomes. In addition, we propose experimental studies using mouse oocytes to examine the factors that influence the mammalian female meiotic process. These experimental studies make use of mouse mutants and recently developed culture systems for the in vitro growth of murine oocytes as model systems for the study of age-related changes in the human meiotic process. Finally, the possibility that the early cleavage divisions of the mammalian embryo are prone to non-disjunction errors is addressed using a murine mutation with a high level of mitotic non-disjunction. The combined data from the proposed studies will provide information on the mechanism(s) responsible for the human maternal age effect. Ultimately this knowledge may be useful in refining the current procedures for human assisted reproduction and/or in designing programs for clinical intervention to provide women over the age of 35 with increased likelihood of achieving a normal pregnancy.

染色体异常概念的可能性随着年龄的增长而显着增加，并且是女性生育能力降低的促成因素。 这些错误对人类健康的后果是深远的。 最常见的异常类型，非整倍性，是我们物种智力低下和妊娠失败的主要原因。 年龄效应的基础仍然未知，但是最近的分子研究表明，减数分裂I（MI，同源染色体分离的时间）是大多数减数分裂误差起源的关键时间点。 在此提案中，我们概述了人类卵母细胞的直接研究，以检查非分离机理和单个人类染色体的年龄关联。 此外，我们建议使用小鼠卵母细胞研究影响哺乳动物女性减数分裂过程的因素。 这些实验研究利用了小鼠突变体和最近开发的培养系统，用于鼠卵母细胞体外生长，作为研究人类减数分裂过程中与年龄相关的变化的模型系统。 最后，使用具有高丝分裂非分离的鼠突变来解决哺乳动物胚胎的早期裂解分裂的可能性。拟议研究的合并数据将提供有关负责人类年龄效应的机制的信息。 最终，这些知识可能有助于完善人类辅助繁殖的当前程序和/或设计临床干预计划，以向女性提供35岁以上的妇女，并增加了正常妊娠的可能性。