Mechanisms underlying sex-dependent pregnancy outcomes caused by fetal and maternal genomic instability

胎儿和母体基因组不稳定引起的性别依赖性妊娠结局的机制

• 批准号: 10391992
• 负责人: John C Schimenti
• 金额: $ 34.65万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-14 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10391992
• 关键词: Address; Adult; Affect; Alleles; Antiinflammatory Effect; Automobile Driving; Biological Assay; Cells; Cessation of life; Complex; Congenital Abnormality; Coupled; Couples; Cytoplasm; DNA; DNA Damage; DNA Repair Gene; DNA Sequence Alteration; DNA biosynthesis; Data; Decidua; Decidua Basalis; Defect; Development; Disease; Embryo; Embryonic Development; Endocrine; Environmental Exposure; Epigenetic Process; Extravasation; Female; Fetal Growth; Fetal Growth Retardation; Fetus; Functional disorder; Gases; Genes; Genetic; Genetic Transcription; Genome; Genomic Instability; Genomics; Genotype; Giant Cells; Goals; Growth; Immune; Individual; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Innate Immune System; Interferons; MCM2 gene; Mitochondria; Mitochondrial DNA; Mitochondrial RNA; Modeling; Modification; Molecular; Mothers; Mus; Mutant Strains Mice; Mutation; Natural Immunity; Nuclear; Nutrient; Oocytes; Oogenesis; Organ; Outcome; Pathway interactions; Placenta; Placental Insufficiency; Polyploidy; Pre-Eclampsia; Predisposition; Pregnancy; Pregnancy Outcome; Pregnancy loss; RNA; RNA Virus Infections; Recurrence; Research; Sex Bias; Signal Transduction; Spontaneous abortion; Stimulator of Interferon Genes; Testing; Testosterone; Tissues; Translating; Uterus; Work; adverse pregnancy outcome; cell type; experimental study; fetal; fetus cell; genetic testing; helicase; imprint; inflammatory marker; insight; male; micronucleus; mouse genetics; mutant; novel; nutrition; obstetrical syndromes; oocyte quality; prevent; replication stress; senescence; sensor; sex; sexual dimorphism; single-cell RNA sequencing; stem; trophoblast; wasting

Adverse pregnancy outcomes can be the consequence of defects in several factors, such fetal or maternal genetics, environmental exposures, uterine dysfunction, preeclampsia, nutrition, infection, inflammation, and placental insufficiency. Development of a healthy placenta from trophectoderm precursors enables proper nutrient, gas and waste exchange between the fetus and mother. Additionally, maternal and placenta-intrinsic inflammation at the interface must be controlled to protect the fetus. This project addresses how genomic instability (GIN) during oogenesis and embryogenesis can cause sexually dimorphic pregnancy outcomes, and how the placenta may be especially susceptible to this condition. Research into this underappreciated cause of adverse pregnancy outcomes is motivated by findings that female mouse embryos are dramatically more prone to lethality when bearing certain GIN-causing mutations of DNA replication or repair genes. In one such model that will be utilized in this project, the female-biased lethality was due to increased susceptibility to inflammation, whereas male embryos were protected by the anti-inflammatory effects of testosterone. Preliminary data implicate the placenta as the sensitive tissue underlying the embryonic death. Remarkably, this sex-biased lethality occurred only if the dam also had a GIN genotype. The goals of this project are to understand the tissue(s), cells, and mechanisms driving GIN-induced lethal inflammation. This will be accomplished using the power of mouse genetics, genomics, and embryo manipulation. Aim 1 will test whether the placenta, the embryo, or both, are responsible for female-biased lethality. We hypothesize that the highly polyploid trophoblast giant cells may be especially sensitive to compromised DNA replication and GIN, triggering innate inflammation. Aim 2 addresses why oocytes must come from high GIN mothers for the sex bias to occur in fetuses bearing the mutant lethal genotype. Preliminary experiments implicate that such dams produce oocytes with compromised mitochondria, and this hypothesis will be tested using mitochondrial augmentation and -omics analyses. Aim 3 seeks to identify the molecular basis of lethal embryonic inflammation, with a focus on triggers of innate immunity. A combination of genetic and molecular assays will be used to test the hypothesis that nuclear GIN leads to mitochondrial RNA and DNA leakage, activating a pathway(s) that stimulates transcription of inflammation-driving interferon genes. Overall, if successful, the results will be relevant for interpreting and addressing individual cases of recurrent pregnancy loss that may have a basis in intrinsic inflammation during gestation, and provide insights into underappreciated mechanisms causing adverse pregnancy outcomes including miscarriage and intrauterine growth retardation.

不良妊娠结局可能是几个因素缺陷的结果，如胎儿或母体 遗传学、环境暴露、子宫功能障碍、先兆子痫、营养、感染、炎症和 胎盘功能不全从滋养外胚层前体发育健康的胎盘， 胎儿和母亲之间的营养、气体和废物交换。此外，母体和胎盘固有 必须控制界面处的炎症以保护胎儿。这个项目解决了基因组如何 卵子发生和胚胎发生期间的不稳定性（GIN）可导致性二态妊娠结局， 以及胎盘如何特别容易受到这种情况的影响。研究这个被低估的 不良妊娠结果的原因是由于发现雌性小鼠胚胎显着 当携带某些导致GIN的DNA复制或修复基因突变时，更容易致命。在一个 在本项目中将使用的此类模型中，雌性偏倚致死率是由于易感性增加所致 而雄性胚胎则受到睾酮抗炎作用的保护。 初步数据表明胎盘是胚胎死亡的敏感组织。值得注意的是， 只有当母鼠也具有GIN基因型时，才会发生这种性别偏向的致死性。该项目的目标是 了解组织，细胞和驱动GIN诱导的致命炎症的机制。这将是 利用小鼠遗传学、基因组学和胚胎操作的力量来完成。目标1将测试 胎盘、胚胎或两者都是造成雌性偏性致死的原因。我们假设 多倍体滋养层巨细胞可能对受损的DNA复制和GIN特别敏感， 引发先天性炎症目的2说明了为什么卵母细胞必须来自高GIN母亲的性别 在携带突变致死基因型的胎儿中发生偏倚。初步实验表明， 产生线粒体受损的卵母细胞，这一假设将用线粒体 扩增和组学分析。目的3旨在确定致死性胚胎性 炎症，重点是先天免疫的触发因素。基因和分子检测的结合将 用于检验核GIN导致线粒体RNA和DNA泄漏，激活线粒体DNA的假设。 刺激炎症驱动干扰素基因转录的途径。 总体而言，如果成功，其结果将有助于解释和处理个别的经常性 妊娠丢失可能与妊娠期间的内在炎症有关，并提供了以下方面的见解： 未被充分认识的机制导致不良妊娠结局，包括流产和宫内 生长迟缓