Gene-environment interactions in epithelial morphogenesis

上皮形态发生中的基因-环境相互作用

基本信息

批准号：
9912166
负责人：
YING XIA
金额：
$ 46.42万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
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/9912166
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 Epithelium 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 Intervention Preventive measure Public Health Receptor Activation Receptor Signaling Regulation Repression Risk Risk Assessment Role Signal Pathway Signal Transduction Spottings Stimulus Stress 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 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 programs response small hairpin RNA tool translational approach upstream kinase

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 Epithelium 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 Intervention Preventive measure Public Health Receptor Activation Receptor Signaling Regulation Repression Risk Risk Assessment Role Signal Pathway Signal Transduction Spottings Stimulus Stress 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 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 programs response small hairpin RNA tool translational approach upstream kinase

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项目摘要

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/摘要类似二恶英的化学物质（DLC）是全球环境污染物，对健康构成重大健康威胁人类。人们普遍认为，基因组成是暴露暴露风险的主要决定因素，但对疾病的易患性疾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将发育组织敏化的基因突变毒性。该模型基于胚胎眼睑闭合，这是所有哺乳动物中保守的发育过程。眼睑闭合是在胚胎发生中发生的主要形态发生事件，由眼睑上皮细胞导致相对的眼睑融合。眼睑闭合的失败不是威胁生命的但是，新生儿的出生时会睁开眼睛（EOB）表型。 EOB表型很容易发现，并且因此，在大量的遗传突变菌株中发现。多年来，EOB小鼠充当强大的工具，以阐明上皮形态发生的遗传网络和信号传导机制。在此模型的基础上，我们已经确定了眼睑调节中的MAP3K1-JNK信号级联关闭。我们最近应用了该系统来研究对环境化学化学的遗传敏感性毒性，并表明MAP3K1基因杂合性和子宫二恶英暴露阻滞的组合眼睑闭合，而单独的条件都没有有害作用。这些观察表明眼睑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。电流提案将通过检验假设来调查三个特定目的GXE相互作用的机制遗传和环境应力融合了抑制MAP3K1-JNK途径的破坏上皮形态发生。 AIM 1将确定二恶英信号与MAP3K1-之间的分子联系 JNK途径。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睑发育中的这些信号之间。结果将定义一种新的机制，其中遗传和环境因素针对单独的信号通路，但途径的串扰导致不利结果。 AIM 2将确定二恶英毒性中MAP3K1途径的新遗传成分。结果将导致对容易受到化学毒性的遗传条件的机械理解。 AIM 3将桥接通过利用MAP3K1的识别，基本研究和翻译研究之间的差距先天性眼睛结构异常的患者的杂合性。我们将使用特定于患者的诱导多能干细胞（IPSC）检查在体外分化过程中的二恶英处理是否导致 MAP3K1信号传导和上皮细胞迁移受损的失活，这是与眼睑闭合缺陷。结果将使我们更近一步，将小鼠的机械发现转换为了解人类疾病。该项目提出的研究将提供有关机制的关键见解 GXE相互作用和实验性范式研究了基础出生缺陷的多因素病因。