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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要许多女性都在与不孕症作斗争，只有大约 30% 的妊娠能够顺利分娩，并且其余的则因自然流产而失败，其中大多数与非整倍体。这里我们使用嵌合非整倍体小鼠模型来研究染色体的影响胚胎发育在植入前、植入前后和植入后早期阶段的嵌合现象。我们之前已经证明，非整倍性会在不同的邻近组织中产生两种不同的反应植入前胚胎的发育：胚胎外滋养外胚层的细胞周期延迟，这将建立胎盘和将形成胎儿的内细胞团的凋亡。我们现在将确定大多数持续进入植入阶段的非整倍体细胞的命运，以及在许多情况下如何这些可以在不影响植入形态发生和相关的情况下消除多能状态的转变。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，以确保发育并确定不同细胞所采用的机制植入后组织应对非整倍性并保护产生所有细胞的多能谱系胚层和种系。对不同生物体的研究表明，全球基因表达和翻译水平与非整倍性程度相关，我们将确定是否存在非整倍性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胚胎并确定 p53 和 mTOR 在此过程中的作用。我们的研究将揭示发育中的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。它将通过建立一个工作平台来为诊所的 IVF 策略提供信息了解在什么情况下人类胚胎被诊断为嵌合体应该或不应该被丢弃。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。