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: 10557129
• 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/10557129
• 关键词: Abnormal Cell; Aneuploid Cells; Aneuploidy; Apoptosis; Autophagocytosis; Biological; Biological Models; Cell Cycle; Cells; Chromosomes; Clinic; Compensation; 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; Placenta; Pregnancy; Pregnancy Outcome; Pregnancy loss; Probability; Process; Proliferating; Proteomics; Reproductive Biology; Role; Shapes; Spontaneous abortion; TP53 gene; Technology; Tissues; Translations; Woman; Work; biological adaptation to stress; blastocyst; blastomere structure; coping; early pregnancy loss; embryo cell; embryo culture; fetus cell; fitness; implantation; improved outcome; insight; mosaic; mouse model; natural Blastocyst Implantation; novel; pharmacologic; pluripotency; 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 许多妇女与不孕不育作斗争，只有大约30%的怀孕进展到活产和 其余的失败是由于自然流产，其中大部分与 非整倍体。在这里，我们使用小鼠的嵌合体非整倍体模型来研究染色体的影响 植入前、围产期和植入后早期胚胎发育的嵌合论。 我们以前已经证明，非整倍体在不同的邻近组织中会导致两种不同的反应 着床前胚胎：胚胎外滋养外胚层细胞周期延迟，将建立 胎盘和内细胞团中的细胞凋亡将建立胎儿。我们现在将确定 大多数持续到着床阶段的非整倍体细胞的命运，以及在许多情况下， 可以在不影响植入形态发生和相关的情况下消除这些 多能状态下的过渡。我们将确定胚胎能在多大程度上补偿 对于丢失的非整倍体细胞，以确保发育并确定不同 植入后组织以应对非整倍体并保护产生ALL的多能血统 生殖层和生殖系。因为在不同生物体中的研究表明，全球基因表达和 翻译水平与非整倍体的程度相关，我们将确定非整倍体在 胚胎导致蛋白质组失衡，导致一系列常见的蛋白质毒性应激反应， 诱导自噬。我们将阐明自噬在消除非整倍体细胞中的作用。 并确定P53和mTOR在这一过程中的作用。我们的研究将有助于 在发育过程中非整倍体和二倍体细胞之间的竞争，并将揭示新的途径 调节胚胎生长和可塑性。它将通过建立一个有效的 了解在哪些情况下应该或不应该诊断为嵌合体的人类胚胎 被丢弃了。这将使人们能够更准确地评估马赛克的发展潜力 并允许开发更好的方法来评估成功的可能性 怀孕了。