Age and molecular mechanisms contributing to aneuploidy in oocytes

非整倍体的增加是人类女性生育率从35年开始显著下降的主要原因 女性卵子中非整倍体的发生率在40岁左右增加到35%，并且 可能更高，因为导致自然流产的非整倍体通常不被识别。 非整倍体是妊娠丢失的主要原因，当发育到足月时，一个更严重的来源 发育障碍和精神发育迟滞。大多数非整倍体与母体增加有关 年龄是由于减数分裂过程中出现的不分离和减数分裂错误所致。值得注意的是，潜在的 导致与年龄相关的非整倍体增加的分子机制尚不清楚。结果 我们之前的研究表明，纺锤体组装检查点(SAC)和着丝粒的缺陷 功能可能是年龄相关的非整倍体增加的原因。SAC是一条途径 通过阻止后期的开始直到所有的染色体都正确的来防止分离错误 主轴上的附件。以小鼠为模型系统，对活体单个卵母细胞进行成像， 目的1将检验卵母细胞中SAC的稳健性随着年龄的增加而降低的假设。另一道工序 防止错误的方法是调节运动中枢和纺锤体微管之间的连接，从而导致 染色体连接正确的纺锤体。我们的表情分析也揭示了表情的变化 与染色体聚集有关的动粒蛋白。特定目标2将检查染色体 正确的纺锤体微管-动粒连接的聚集和分子机制，以及 在从老年雌性获得的卵母细胞中，测试这些机制受到损害的假设。特定的 Aim 3将测试从我们的表达谱中识别的特定着丝粒和着丝粒蛋白 在心肌梗死期间，需要进行准确的染色体分离研究。本报告中提出的实验结果 应用程序将提供大量关于与年龄相关的分子碱基的信息 非整倍体发生率的增加以及精确染色体所需的基本机制 种族隔离。这些发现可能建议进行实验干预，以减轻 从老年妇女那里获得的卵母细胞变成非整倍体。

An increase in aneuploidy is a major cause for the marked decline in human female fertility commencing 35 years-of-age; the incidence of aneuploidy in eggs from women increases to 35% around 40 years-of-age, and is likely to be even higher because aneuploidy leading to a spontaneous abortion is frequently not recognized. Aneuploidy is a leading cause of pregnancy loss, and when development goes to term, an aggravating source of developmental disabilities and mental retardation. Most aneuplodies associated with increased maternal age are due to non-disjunction and meiotic errors that occur during meiosis. Remarkably, the underlying molecular mechanisms that lead to the age-associated increase in aneuploidy are poorly understood. Results of our previous studies suggest that defects in the spindle assembly checkpoint (SAC) and kinetochore function are likely causes for the age-associated increase in aneuploidy. The SAC is one pathway that prevents segregation errors by blocking the onset of anaphase until all chromosomes make proper attachments to the spindle. Using mouse as a model system and imaging of live individual oocytes, Specific Aim 1 will test the hypothesis that the robustness of the SAC in oocytes decreases with age . Another process that prevents errors is regulation of connections between kinetochores and spindle microtubules that results in a spindle with chromosomes correctly attached. Our expression profiling also reveals changes in expression of kinetochore proteins involved in chromosome congression. Specific Aim 2 will examine chromosome congression and molecular mechanisms that underlie correct spindle microtubule-kinetochore attachment, and test the hypothesis that these mechanisms are compromised in oocytes obtained from old females. Specific Aim 3 will test whether specific centromere and kinetochore proteins identified from our expression profiling studies are required for accurate chromosome segregation during MI. Results of experiments proposed in this application will provide a plethora of information regarding molecular bases that underlie the age-associated increase in the incidence of aneuploidy, as well as basic mechanisms required for accurate chromosome segregation. Such findings may suggest experimental interventions that could alleviate the propensity of oocytes obtained from older women to become aneuploid.