Gene-environment interactions in epithelial morphogenesis

上皮形态发生中的基因-环境相互作用

• 批准号: 10382399
• 负责人: YING XIA
• 金额: $ 45.49万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-09 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382399
• 关键词: Actins; Adverse effects; Affect; Animal Model; Aryl Hydrocarbon Receptor; Attenuated; Basic Science; Biological; Biological Process; Birth; CRISPR/Cas technology; Cells; Chemicals; Complex; Congenital Abnormality; Custom; Defect; Development; Developmental Process; Dioxins; Disease; Embryo; Embryonic Development; Environment; Environmental Impact; Environmental Pollutants; Environmental Risk Factor; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Etiology; Event; Experimental Models; Exposure to; Eye; Eye diseases; Eyelid structure; Failure; Fetus; Funding; Gene Mutation; Genes; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genetic Risk; Goals; Grant; Health; Health Benefit; Heterozygote; Human; Impairment; In Vitro; Individual; Lead; Libraries; Link; MAP Kinase Gene; MAP3K1 gene; MAPK8 gene; Mammals; Mediating; Mediator of activation protein; Modeling; Molecular; Morphogenesis; Movement; Mus; Mutant Strains Mice; Mutation; National Institute of Environmental Health Sciences; Newborn Infant; Pathway interactions; Patients; Phenotype; Play; Predisposition; Preventive measure; Public Health; Receptor Activation; Receptor Signaling; Regulation; Repression; Risk; Risk Assessment; Role; Signal Pathway; Signal Transduction; Spottings; Stimulus; Structural Congenital Anomalies; Structural defect; System; Testing; Tissues; Toxic effect; Translating; Translational Research; Work; adverse outcome; base; cell motility; complement system; disease phenotype; disorder risk; environmental chemical; environmental stressor; follow-up; functional outcomes; gene environment interaction; gene function; genetic approach; genetic makeup; global environment; human disease; in utero; in vivo; individualized prevention; induced pluripotent stem cell; insight; men; mouse model; mutant; novel; overexpression; personalized intervention; programs; response; small hairpin RNA; tool; translational approach; upstream kinase

Project Summary/Abstract The dioxin-like chemicals (DLCs) are global environmental pollutants that pose a significant health threat to humans. It is widely believed that the genetic make-up is a major determinant of disease risk from exposure, but the actual gene-environment mechanisms that predispose individuals to disease are poorly understood. We have developed a mouse model to investigate gene mutations that sensitize developmental tissues to dioxin toxicity. The model is based on embryonic eyelid closure, a developmental process conserved in all mammals. Eyelid closure is a major morphogenetic event occurring in late embryogenesis, driven by forward movement of the eyelid epithelial cells leading to fusion of the opposing eyelids. Failure of eyelid closure is not life threatening but results in an eye open at birth (EOB) phenotype in the newborns. The EOB phenotype is easy to spot, and consequently is found in a large number of genetic mutant strains. Over the years, the EOB mice serve as a powerful tool to elucidate the genetic network and signaling mechanisms underlying epithelium morphogenesis. Building on this model, we have identified the MAP3K1-JNK signaling cascades in the regulation of eyelid closure. We recently applied this system to investigate the genetic susceptibility to environmental chemical toxicity, and showed that the combination of Map3k1 gene heterozygosity and in utero dioxin exposure blocks eyelid closure whereas neither condition alone has a detrimental effect. These observations suggest that eyelid closure defect can be a multifactorial disorder resulting from gene-environment (GxE) interactions. The current proposal will investigate in three Specific Aims the mechanisms of GxE interactions by testing the hypothesis that genetic and environmental stresses converge on repression of the MAP3K1-JNK pathway to disrupt epithelial morphogenesis. Aim 1 will determine the molecular link between the dioxin signals and the MAP3K1- JNK pathways. Guided by preliminary findings, we will test whether the EGFR pathway mediates the crosstalk between these signals in eyelid development. Results will define a novel mechanism where the genetic and environmental factors target separate signaling pathways, but the crosstalk of the pathways leads to adverse outcomes. Aim 2 will identify novel genetic components of the MAP3K1 pathway in dioxin toxicity. Results will lead to a mechanistic understanding of the genetic conditions susceptible to chemical toxicity. Aim 3 will bridge the gap between basic and translational research by taking advantage of the identification of MAP3K1 heterozygosity in a patient with congenital eye structural abnormalities. We will use patient-specific induced pluripotent stem cells (iPSCs) to examine whether dioxin treatment during in vitro differentiation leads to inactivation of MAP3K1 signaling and impaired epithelial cell migration, which are biological endpoints linked to defective eyelid closure. Results will bring us a step closer to translate mechanistic discoveries in mice to understanding human diseases. Studies proposed in this project will provide critical insights into the mechanisms of GxE interactions and an experimental paradigm to study multifactorial etiology underlying birth defects.

项目摘要/摘要 二恶英类化合物(DLC)是全球性环境污染物，对人类健康构成重大威胁。 人类。人们普遍认为，基因构成是暴露于环境中的疾病风险的主要决定因素，但 人们对导致个体患病的实际基因环境机制知之甚少。我们 已经开发了一种小鼠模型来研究使发育组织对二恶英敏感的基因突变 毒性。该模型基于胚胎眼皮闭合，这是一种在所有哺乳动物中都保守的发育过程。 眼睑闭合是发生在胚胎发育晚期的一个主要的形态发生事件，由眼睑的前移驱动 眼皮上皮细胞导致对侧眼皮融合。眼皮闭合失败不会危及生命 但会导致新生儿出生时睁眼(EOB)表型。EOB表型很容易识别，而且 因此，在大量的基因突变菌株中发现了该基因。多年来，EOB小鼠充当了 这是阐明上皮细胞形态发生的遗传网络和信号机制的有力工具。 在这个模型的基础上，我们已经确定了MAP3K1-JNK信号通路在眼皮调节中的作用 结案了。我们最近应用这个系统来研究环境化学物质的遗传易感性。 毒性，并表明MAP3K1基因杂合性和宫内二恶英暴露相结合会阻断 眼皮关闭，而这两种情况本身都不会产生有害的影响。这些观察表明，眼皮 闭合缺陷可能是由基因-环境(GxE)相互作用引起的多因素疾病。海流 Proposal将通过检验假设来研究GxE相互作用的三个具体目标 遗传和环境压力集中在MAP3K1-JNK途径的抑制上以破坏 上皮形态发生。目标1将确定二恶英信号和MAP3K1之间的分子联系- JNK小路。在初步发现的指导下，我们将测试EGFR途径是否介导了串扰 在眼皮发育的这些信号之间。结果将定义一种新的机制，其中遗传和 环境因素针对不同的信号通路，但这些通路的串扰导致不利的 结果。目的2鉴定MAP3K1途径在二恶英毒性中的新的遗传成分。结果将 导致对易受化学毒性影响的遗传条件的机械性理解。AIM 3将架起桥梁 利用MAP3K1的鉴定优势在基础研究和翻译研究之间的差距 先天性眼结构异常患者的杂合性。我们将使用特定于患者的诱导 多能干细胞(IPSCs)在体外分化过程中检测二恶英处理是否会导致 MAP3K1信号失活和上皮细胞迁移受损，这是与 有缺陷的眼皮闭合。结果将使我们更近一步，将老鼠的机械发现转化为 了解人类疾病。该项目中提出的研究将提供对这些机制的重要见解。 GxE交互作用和研究出生缺陷背后的多因素病因的实验范式。