Biological mechanisms that eliminate aneuploid cells from a mosaic conceptus in the mouse model system

从小鼠模型系统中的嵌合体概念中消除非整倍体细胞的生物学机制

• 批准号: 10379454
• 负责人: Magdalena Zernicka-Goetz
• 金额: $ 51.88万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10379454
• 关键词: Abnormal Cell; Address; Aneuploid Cells; Aneuploidy; Apoptosis; Autophagocytosis; Biological; Biological Models; Cell Cycle; Cells; Centers for Disease Control and Prevention (U.S.); Chromosomes; Clinic; Conceptus; Congenital Abnormality; Defect; Development; Diagnosis; Diploid Cells; Disease; Embryo; Embryonic Development; Ensure; Epigenetic Process; FRAP1 gene; Failure; Fertility; Fertilization in Vitro; Fetus; Foundations; Gene Expression; Genetic; Germ Cells; Germ Layers; Germ Lines; Growth; Human; Implant; Infertility; Inner Cell Mass; Knowledge; Light; Live Birth; Metabolism; Methods; Modeling; Morphogenesis; Morphology; Mosaicism; Mothers; Mus; National Institute of Child Health and Human Development; Organism; Pathway interactions; Pharmacology; Placenta; Pregnancy; Pregnancy Outcome; Pregnancy loss; Probability; Process; Proteomics; Reproductive Biology; Role; Shapes; Side; Spontaneous abortion; TP53 gene; Tissues; Translations; Woman; Work; biological adaptation to stress; blastocyst; early pregnancy loss; embryo cell; embryo culture; fetus cell; fitness; implantation; improved outcome; insight; mouse model; natural Blastocyst Implantation; novel; pluripotency; preimplantation; prevent; proteostasis; proteotoxicity; reproductive success; response; spatiotemporal; three-dimensional modeling; transcriptome

Project Summary Many women struggle with infertility with only around 30% of pregnancies progressing to live birth and the remainder failing through spontaneous abortions, the majority of which are associated with aneuploidy. Here we use a mouse model for mosaic aneuploidy to study the effects of chromosome mosaicism on development of the conceptus through the pre-, peri-and early post-implantation stages. We have previously shown that aneuploidy results in two different responses in different adjacent tissues of the pre-implantation embryo: cell cycle delay in the extra-embryonic trophectoderm that will establish the placenta and apoptosis in the inner cell mass that will establish the foetus. We will now determine the fate of the majority of aneuploid cells that persist into implantation stages and how, in many cases, these can be eliminated without compromising implantation morphogenesis and the associated transition in the state of pluripotency. We will determine the extent to which the embryo can compensate for lost aneuploid cells to ensure development and determine the mechanisms employed by different post-implantation tissues to cope with aneuploidy and protect the pluripotent lineage that generates all germ layers and germline. As studies in diverse organisms indicate that global gene expression and translation levels correlate with the degree of aneuploidy, we will determine whether aneuploidy in the embryo results in proteomic imbalance leading to a common set of proteotoxic stress responses that induce autophagy. We will elucidate the role of autophagy in the elimination of aneuploid cells from the embryo and determine the roles of p53 and mTOR in this process. Our study will shed light onto competition between aneuploid and diploid cells in development and will uncover new pathways that regulate embryo growth and plasticity. It will inform IVF strategies in the clinic by building a working knowledge of circumstances in which human embryos diagnosed as mosaic should or should not be discarded. It will enable a more accurate assessment of the developmental potential of mosaic aneuploid embryos and permit the development of better methods to assess the probability of successful pregnancy.

项目摘要 许多妇女因不育而挣扎，只有30％的怀孕才能实现生命和 其余因自发堕胎而失败，其中大多数与 非整倍性。在这里，我们使用小鼠模型用于镶嵌性非整倍性来研究染色体的作用 通过前，周期和早期植入后阶段进行概念发展的镶嵌。 我们先前已经表明，非整倍性在不同的相邻组织中产生了两种不同的反应 植入前的胚胎：外胚外滋养剂的细胞周期延迟将建立 内部细胞质量的胎盘和凋亡将建立胎儿。现在我们将确定 大多数非整倍体细胞的命运，这些细胞一直持续到植入阶段，在许多情况下，如何 可以消除这些而不会损害植入形态发生和相关的 多能状态的过渡。我们将确定胚胎可以补偿的程度 对于丢失的非整倍体细胞，以确保开发和确定不同的机制 植入后组织以应对非整倍性并保护生成所有的多能谱系 生殖层和种系。随着各种生物的研究表明，全球基因表达和 翻译水平与非整倍性的程度相关，我们将确定非整倍性是否在 胚胎会导致蛋白质组学失衡，从而导致一组常见的蛋白质应激反应 诱导自噬。我们将阐明自噬在消除非整倍体细胞中的作用 胚胎并确定p53和mTOR在此过程中的作用。我们的研究将阐明 非整倍体和二倍体细胞之间的竞争，并将发现新的途径 调节胚胎生长和可塑性。它将通过建立工作来告知诊所中的IVF策略 了解人类胚胎被诊断为马赛克的情况应该或不应是 丢弃。它将能够更准确地评估马赛克的发育潜力 非整倍体胚胎，并允许开发更好的方法来评估成功的可能性 怀孕。