Signaling mechanisms of gene-environment interactions in female reproductive

女性生殖基因-环境相互作用的信号机制

• 批准号: 10594545
• 负责人: YING XIA
• 金额: $ 20.25万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594545
• 关键词: Abdominal Pain; Adult; Affect; Aryl Hydrocarbon Receptor; Biological Process; Cell Culture Techniques; Cessation of life; Childbirth; Clinical; Complex; Congenital Abnormality; Congenital Disorders; Coupled; Cyclic AMP-Dependent Protein Kinases; Data; Defect; Development; Developmental Toxicant; Dioxins; Disease; Dose; Embryo; Environment; Environmental Exposure; Environmental Pollutants; Environmental Risk Factor; Epithelial Cells; Epithelium; Etiology; Exposure to; Female; Future; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Diseases; Genetic Risk; Genetic study; Goals; Histology; Human; Immunohistochemistry; Incidence; Infertility; Investigation; Knockout Mice; Knowledge; Laboratories; Left; Link; Live Birth; MAP Kinase Gene; MAP3K1 gene; Mediating; Menstruation; Molecular; Molecular Genetics; Morphogenesis; Mus; Mutant Strains Mice; Mutation; Nature; Pathway interactions; Patients; Periodicals; Phenotype; Pregnancy; Puberty; Regulation; Reporter; Repression; Research; Risk; Severities; Sexual Development; Signal Pathway; Signal Transduction; Structure of paramesonephric duct; Testing; Tetrachlorodibenzodioxin; Toxic effect; Vagina; WNT Signaling Pathway; Women' s Health; congenital anomaly; developmental disease; developmental toxicity; experimental study; falls; gene environment interaction; genetic approach; genetic makeup; genetic risk factor; high risk; human disease; hymen; in vivo; laser capture microdissection; loss of function; mouse genetics; mouse model; mutant; novel; prenatal exposure; prevent; reproductive; reproductive tract; toxicant; transcription factor; transcriptome

Project Summary/Abstract Congenital anomalies of the female reproductive tract (FRT) occur in approximately 5% of live birth in females. These conditions are congenital, but often go undetected until puberty when the patients fail to menstruate and suffer periodic lower abdominal pain; if left untreated, they lead to infertility and death during pregnancy or childbirth. The anomalies have complex clinical presentations with the etiology still poorly understood. Given that FRT anomaly has both familial and sporadic cases, the causative agents are likely to be complex, involving genes, environmental factors, or both. To date, the multifactorial etiology and the mechanisms of gene- environment interactions in congenital FRT anomalies are largely unexplored. We have recently identified Map3k1 loss-of-function as a novel genetic condition of congenital FRT anomaly - Map3k1 inactivation in mice is associated with developmental FRT defects and infertility in females. Map3k1 encodes a protein kinase, an upstream regulator of the MAPK pathways that crosstalk with diverse environmental signals and developmental pathways. We have shown that Map3k1 loss-of-function could aggravate the developmental toxicity of dioxin, a ubiquitous environmental pollutant. Moreover, dioxin is also a reproductive toxicant that induces FRT defects similar to those observed in the Map3k1-null mice. In the current proposal, we will test the hypothesis, supported by preliminary evidence, that Map3k1 mutation plus dioxin constitute the multifactorial etiology that converges on WNT inhibition to cause congenital FRT anomalies. We will use an in vivo genetic approach to examine whether Map3k1 mutation plus dioxin exposure potentiate the incidence and/or the severity of FRT defective phenotypes, whether the dioxin receptor, Ah receptor (AHR), mediates FRT toxicity, and whether the gene- environment interactions repress WNT activity. We will combine mouse genetics, molecular histopathogenesis, and laser capture microdissection coupled with global gene expression profiling to delineate the biological processes and molecular pathways affected by genetic and environmental insults in FRT development. We aim to understand the molecular details of how gene-environment interactions contribute to congenital female reproductive anomaly, with the long-term future goal of using this knowledge to prevent and treat this prevalent devastating disease affecting women’s health and reproductivity.

项目概要/摘要 大约 5% 的女性活产会出现女性生殖道先天性异常 (FRT)。 这些情况是先天性的，但通常直到青春期才被发现，此时患者没有月经，并且 周期性下腹疼痛；如果不及时治疗，它们会导致不孕和怀孕期间死亡或 分娩。这些异常具有复杂的临床表现，其病因仍知之甚少。鉴于 FRT异常既有家族性病例，也有散发性病例，病因可能很复杂，涉及 基因、环境因素或两者兼而有之。迄今为止，多因素病因学和基因机制 先天性 FRT 异常中的环境相互作用很大程度上尚未被探索。我们最近确定了 Map3k1 功能丧失是先天性 FRT 异常的一种新遗传状况 - 小鼠中 Map3k1 失活 与发育性 FRT 缺陷和女性不孕有关。 Map3k1 编码蛋白激酶， MAPK 通路的上游调节因子，与多种环境信号和发育信号串扰 途径。我们已经证明 Map3k1 功能丧失可能会加剧二恶英的发育毒性，二恶英是一种 普遍存在的环境污染物。此外，二恶英也是一种生殖毒物，可诱发FRT缺陷 与在 Map3k1 缺失小鼠中观察到的结果相似。在当前的提案中，我们将测试假设，得到支持 初步证据表明，Map3k1突变加上二恶英构成了多因素汇聚的病因 抑制 WNT 导致先天性 FRT 异常。我们将使用体内遗传方法来检查 Map3k1 突变加上二恶英暴露是否会增加 FRT 缺陷的发生率和/或严重程度 表型、二恶英受体、Ah 受体 (AHR) 是否介导 FRT 毒性，以及该基因是否 环境相互作用抑制 WNT 活动。我们将结合小鼠遗传学、分子组织病理学、 激光捕获显微切割结合全局基因表达谱来描绘生物 FRT 发展中受遗传和环境损害影响的过程和分子途径。我们的目标 了解基因-环境相互作用如何影响先天性女性的分子细节 生殖异常，未来的长期目标是利用这些知识来预防和治疗这种普遍存在的疾病 影响妇女健康和生育能力的毁灭性疾病。