Causes and Consequences of Aneuploidy in HeSCs

HeSC 非整倍体的原因和后果

基本信息

批准号：
10374156
负责人：
Kristina M Godek
金额：
$ 35.13万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
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/10374156
关键词：
Address 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 base blastomere structure chromosome missegregation chromosome number abnormality daughter cell embryo tissue genome integrity human embryonic stem cell improved preimplantation premature preservation prevent quantitative imaging reproductive success response segregation

项目摘要

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.

项目概要/摘要在细胞分裂过程中，染色体必须准确分离，才能产生具有正确染色体的子细胞。染色体数量，而分离错误产生染色体数量异常的非整倍体细胞染色体。在正常人类体细胞中，染色体分离错误和非整倍体很少见。在相比之下，在人类全能和多能胚胎细胞中，减数分裂和有丝分裂错误很常见，导致非整倍体是流产和出生缺陷的主要原因。然而，我们不明白的是对此负责的机制，特别是有丝分裂错误。此外，鉴于如此高的有丝分裂错误率，有人提出，随着发育的进展，二倍体细胞可以战胜非整倍体细胞以建立整倍体胚胎，但这是如何发生的尚不清楚。我们将利用多能技术来解决我们知识中的这些空白人类胚胎干细胞 (hESC) 以及定量成像、化学和基因组学的结合接近。这笔赠款的具体目的是（1）确定负责有丝分裂的途径 hESC 中的染色体分离错误，(2) 以确定 hESC 的 G1 细胞周期结构是否允许对非整倍体的初始耐受性，以及 (3) 确定非整倍体基因组随后如何损害 hESC 对胚胎组织的贡献。总的来说，这些目标检验了我们的总体假设：多能胚胎细胞在支持机制方面与体细胞本质上不同染色体分离保真度及其对非整倍性的反应。此外，这项工作奠定了为我们的长期目标奠定了基础，即确定负责的分子信号传导途径胚胎细胞非整倍性的原因、耐受性和后果，以及制定策略保护培养中生长的胚胎细胞的基因组完整性，以提高生殖和生殖的成功率再生医学疗法。总之，这项工作将揭示潜在的机制胚胎细胞中的非整倍性以及如何最终实现核型稳定性以支持正常人类发展。