Causes and Consequences of Aneuploidy in HeSCs

HeSC 非整倍体的原因和后果

• 批准号: 10612343
• 负责人: Kristina M Godek
• 金额: $ 36.63万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-12 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612343
• 关键词: Abbreviations; Acceleration; Anaphase; Aneuploid Cells; Aneuploidy; Apoptosis; Attention; Automobile Driving; Biological Assay; Cell Cycle; Cell Cycle Arrest; Cell Survival; Cell division; Cells; Chemicals; Chromosome Segregation; Chromosomes; Congenital Abnormality; DNA sequencing; Data; Defect; Development; Diploid Cells; Diploidy; Disadvantaged; Embryo; Foundations; Genome; Genomic approach; Goals; Grant; Human; Human Development; Impairment; Inherited; Karyotype; Kinetochores; Knowledge; Label; Measures; Meiosis; Microtubules; Mitosis; Mitotic; Molecular; Pathway interactions; Pregnancy; Regenerative Medicine; Reproductive Medicine; Signal Pathway; Somatic Cell; Spontaneous abortion; Structure; Teratoma; Testing; Time; Totipotent; Work; blastocyst; blastomere structure; chromosome missegregation; chromosome number abnormality; daughter cell; embryo cell; embryo tissue; embryonic stem cell; genome integrity; human embryonic stem cell; improved; premature; preservation; prevent; quantitative imaging; reproductive success; response; restraint; segregation

PROJECT SUMMARY/ABSTRACT During cell division chromosomes must be accurately segregated to produce daughter cells with the correct numbers of chromosomes whereas segregation errors generate aneuploid cells with abnormal numbers of chromosomes. In normal human somatic cells, chromosome segregation errors and aneuploidy are rare. In contrast, in human totipotent and pluripotent embryonic cells meiotic and mitotic errors are common, resulting in aneuploidy being the leading cause of miscarriages and birth defects. Yet, we do not understand the mechanisms responsible for this, particularly for mitotic errors. Moreover, given such a high mitotic error rate, it is proposed that diploid cells can outcompete aneuploid cells as development progresses to establish euploid embryos, but how this occurs is unknown. We will address these gaps in our knowledge using pluripotent human embryonic stem cells (hESCs) and a combination of quantitative imaging, chemical, and genomics approaches. The specific aims of this grant are (1) to determine the mitotic pathways responsible for chromosome segregation errors in hESCs, (2) to determine if the G1 cell cycle structure of hESCs permits an initial tolerance to aneuploidy, and (3) to determine how an aneuploid genome subsequently impairs hESCs contribution to embryonic tissues. Collectively, these aims test our overarching hypothesis that pluripotent embryonic cells are inherently different from somatic cells with respect to mechanisms that support chromosome segregation fidelity and in their response to aneuploidy. Furthermore, this work lays the foundation for our long-term objectives of identifying the molecular signaling pathways responsible for the causes, tolerance, and consequences of aneuploidy in embryonic cells and for developing strategies that preserve the genome integrity of embryonic cells grown in culture to improve the success of reproductive and regenerative medicine therapies. In conclusion, this work will reveal both the mechanisms underlying aneuploidy in embryonic cells and how karyotype stability is eventually achieved to support normal human development.

项目摘要/摘要 在细胞分裂期间，必须准确隔离染色体，以产生正确的子细胞 染色体的数量，而种族隔误差会产生异倍体细胞，异常数量 染色体。在正常的人体细胞中，染色体分离误差和非整倍性很少见。在 对比，在人类的全能和多能胚细胞中，减数分裂和有丝分裂错误很常见，因此 非整倍性是流产和先天缺陷的主要原因。但是，我们不了解 为此负责的机制，尤其是针对有丝分裂错误。此外，鉴于如此高的有丝分裂错误率， 有人提出，随着发育的发展，二倍体细胞可以胜过非整倍体细胞 胚胎，但是发生这种情况是未知的。我们将使用多能在我们的知识中解决这些差距 人类胚胎干细胞（HESC）以及定量成像，化学和基因组学的组合 方法。这笔赠款的具体目的是（1）确定负责的有丝分裂途径 hESC中的染色体分离误差（2）确定hESC的G1细胞周期结构是否允许 对非整倍性的初始耐受性，（3）确定非整倍体基因组随后如何损害hESCS 对胚胎组织的贡献。总的来说，这些目标检验了我们多元化的总体假设 相对于支持机制，胚胎细胞与体细胞本质上不同 染色体隔离保真度及其对非整倍性的反应。此外，这项工作使 我们确定负责分子信号通路的长期目标的基础 胚胎细胞中非整倍性的原因，耐受性和后果，以及制定策略 保留在培养中生长的胚胎细胞的基因组完整性，以改善生殖和 再生医学疗法。总之，这项工作将揭示两种机制 胚胎细胞中的非整倍性以及如何最终达到核型稳定性以支持正常人 发展。