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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.

项目总结