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

基本信息

批准号：
10704495
负责人：
John C Schimenti
金额：
$ 34.63万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
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/10704495
关键词：
Address Adult Affect Alleles Antiinflammatory Effect Automobile Driving Biological Assay Cells Complex Congenital Abnormality Coupled Couples Cytoplasm DNA DNA Damage DNA Repair Gene DNA Sequence Alteration DNA biosynthesis Data Decidua Defect Development Disease Embryo Embryo Deaths 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 Individual Infection 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 immune cell infiltrate 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

项目摘要

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.

不良怀孕结果可能是几个因素缺陷的结果，例如胎儿或母亲遗传学，环境暴露，子宫功能障碍，先兆子痫，营养，感染，炎症和胎盘不足。从滋养外胚层前体开发健康的胎盘可以适当胎儿和母亲之间的营养，天然气和废物交换。另外，母体和胎盘intrinsic 必须控制界面处的炎症以保护胎儿。该项目解决了基因组如何卵子发生和胚胎发生过程中的不稳定性（GIN）会导致性二态妊娠结局，以及胎盘如何特别容易患这种情况。研究这种未被充分考虑的雌性小鼠胚胎急剧激发了不良怀孕结果的原因在某些DNA复制或修复基因的引起杜松子酒突变时，更容易致死性。一个这种项目将在该项目中使用，女性偏见的致死性是由于易感性提高所致炎症，而雄性胚胎受到睾丸激素的抗炎作用的保护。初步数据将胎盘作为胚胎死亡的敏感组织。值得注意的是这种性偏见的致死性仅在大坝也具有杜松子酒基因型时才发生。该项目的目标是了解组织，细胞和驱动杜松子诱导的致死炎症的机制。这将是使用小鼠遗传学，基因组学和胚胎操纵的力量完成。 AIM 1将测试是否胎盘，胚胎或两者都导致女性偏见的致死性。我们假设高度多倍体滋养细胞巨细胞可能对受损的DNA复制和杜松子酒特别敏感，引发先天炎症。 AIM 2解决了为什么卵母细胞必须来自高级杜松子酒母亲发生突变致死基因型的胎儿发生的偏见。初步实验暗示着这种水坝用损害线粒体产生卵母细胞，该假设将使用线粒体进行检验增强和 - 组合分析。 AIM 3旨在识别致命胚胎的分子基础炎症，重点是先天免疫的触发因素。遗传和分子测定的结合将用于检验核杜松子的假设，核杜松子会导致线粒体RNA和DNA泄漏，激活A 刺激炎症干扰素基因转录的途径。总体而言，如果成功的话，结果将与解释和解决各个复发案例有关怀孕丧失可能在妊娠期间具有内在炎症基础不足的机制导致不良怀孕结果，包括流产和宫内增长迟钝。