Age and molecular mechanisms contributing to aneuploidy in oocytes

导致卵母细胞非整倍性的年龄和分子机制

• 批准号: 7904320
• 负责人: Michael Lampson
• 金额: $ 32.83万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904320
• 关键词: Age; Age-Years; Anaphase; Aneuploidy; Animals; Assisted Reproductive Technology; Biological Models; Cells; Centromere; Chromosome Segregation; Chromosomes; Competence; Defect; Development; Developmental Disabilities; Down Syndrome; Elderly; Ensure; Eukaryotic Cell; Female; Fertility; Grant; Human; Image; Incidence; Individual; Infertility; Intervention; Kinesin; Kinetochores; Lead; Life; Mammals; Maternal Age; Meiosis; Mental Retardation; Microtubules; Mitosis; Mitotic; Molecular; Molecular Profiling; Motor; Mus; Oocytes; Pathway interactions; Pregnancy loss; Process; Protein Kinase; Proteins; Regulation; Role; Signal Transduction; Source; Spontaneous abortion; System; Testing; Time; Woman; Xenopus; age related; anaphase-promoting complex; aurora B kinase; base; egg; human PLK1 protein; human female; inner centromere protein; insight; older women; prevent; protein complex; protein function; public health relevance; reproductive; research study; segregation

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The proposed studies will provide new information regarding molecular mechanisms that underlie the maternal age-associated increase in aneuploidy. The results of these studies will likely impact on the treatment of human infertility and assisted reproduction technologies.

描述(申请人提供)：非整倍体的增加是人类女性生育力从35岁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%，而且很可能更高，因为导致自然流产的非整倍体经常得不到承认。非整倍体是导致妊娠丢失的主要原因，当发育到足月时，会加重发育障碍和智力低下的根源。大多数与母亲年龄增加相关的非整倍体是由于减数分裂过程中发生的不分离和减数分裂错误。值得注意的是，导致非整倍体随年龄增加的潜在分子机制尚不清楚。我们以前的研究结果表明，纺锤体组装检查点(SAC)和着丝粒功能的缺陷可能是年龄相关的非整倍体增加的原因。SAC是防止分离错误的途径之一，它阻止后期的开始，直到所有的染色体都正确地附着在纺锤体上。以小鼠为模型系统，并对活的单个卵母细胞进行成像，特定目标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。另一个防止错误的过程是调节动粒和纺锤体微管之间的连接，从而产生正确连接染色体的纺锤体。我们的表达谱也揭示了参与染色体聚集的动粒蛋白表达的变化。《特殊目的2》将研究染色体聚集和正确的纺锤体微管-着丝粒附着的分子机制，并检验这些机制在从老年雌性获得的卵母细胞中受到损害的假设。特殊目标3将测试从我们的表达谱研究中确定的特定着丝粒和着丝粒蛋白是否需要在心肌梗死期间进行准确的染色体分离。本申请中提出的实验结果将提供大量关于与年龄相关的非整倍体发生率增加的分子基础的信息，以及准确分离染色体所需的基本机制。这些发现可能建议进行实验干预，以减轻从老年女性获得的卵母细胞成为非整倍体的倾向。公共卫生相关性：拟议的研究将提供有关非整倍体母亲年龄相关增加的分子机制的新信息。这些研究的结果可能会对人类不孕不育的治疗和辅助生殖技术产生影响。