Age and molecular mechanisms contributing to aneuploidy in oocytes

非整倍体的增加是从35岁开始人类女性生育力显著下降的主要原因。 40岁左右女性卵子非整倍体的发生率增加到35%， 可能更高，因为导致自然流产的非整倍体通常不被识别。 非整倍体是导致流产的主要原因，当发育到足月时， 发育障碍和智力迟钝。大多数非整倍体与母体 年龄是由于不分离和减数分裂过程中发生的减数分裂错误。值得注意的是， 导致非整倍性年龄相关性增加的分子机制知之甚少。结果 我们以前的研究表明，纺锤体组装检查点（SAC）和动粒缺陷 这些功能可能是年龄相关的非整倍体增加的原因。SAC是一种途径， 通过阻断分裂后期的开始来防止分离错误，直到所有的染色体都正确地 连接到主轴。使用小鼠作为模型系统并对活的单个卵母细胞进行成像， 目的1将检验卵母细胞中SAC的稳健性随年龄而降低的假设。另一个进程 防止错误的是调节着丝粒和纺锤体微管之间的连接， 染色体正确附着的纺锤体。我们的表达谱分析也揭示了表达的变化， 参与染色体聚集的动粒蛋白质。特定目标2将检查染色体 正确的纺锤体微管-动粒附着的基础的聚集和分子机制，以及 测试这些机制在从老年女性获得的卵母细胞中受到损害的假设。具体 目的3将测试是否特定的着丝粒和动粒蛋白质确定从我们的表达谱 在MI期间需要进行精确的染色体分离研究。本文中提出的实验结果 应用程序将提供大量的信息，有关分子基础的年龄相关的 非整倍体发生率的增加，以及准确的染色体所需的基本机制， 种族隔离这些发现可能表明实验性干预可以减轻 从老年妇女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.