Gene-Environment Interactions in Eyelid Morphogenesis

眼睑形态发生中的基因-环境相互作用

• 批准号: 8770085
• 负责人: YING XIA
• 金额: $ 23.78万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8770085
• 关键词: Affect; Alleles; Biological; Cleft Palate; Clinical; Complex; Congenital Abnormality; Data; Defect; Development; Developmental Process; Dioxins; Disease; Dose; Embryo; Embryonic Development; Environment; Environmental Risk Factor; Epidemiology; Epithelial Cells; Epithelium; Etiology; Event; Exposure to; Eye; Eye Abnormalities; Eye Development; Eyelid structure; Failure; Fetal Development; Fetus; Frequencies; Gap Junctions; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Goals; Health Benefit; Healthcare; Hereditary Disease; Human; Incidence; Individual; Intervention; JUN gene; Lead; Lesion; Ligands; Live Birth; MAP Kinase Kinase Kinase; MAPK8 gene; Mammals; Maternal Exposure; Mediating; Modeling; Molecular; Morphogenesis; Mus; Mutant Strains Mice; Nature; Neural Tube Closure; Other Genetics; Palate; Patients; Penetrance; Phenotype; Plant Roots; Play; Population; Predisposition; Pregnancy; Ptosis; Public Health; Regulation; Research; Risk Assessment; Risk Factors; Role; Sampling; Series; Severities; Signal Transduction; Spinal Dysraphism; Staging; Strabismus; Subgroup; Target Populations; Teratogens; Testing; Toxic effect; Type 1 Duane Retraction Syndrome; VAV3 gene; Work; activating transcription factor; base; cell motility; developmental disease; disease phenotype; disorder prevention; environmental agent; environmental intervention; gene environment interaction; genetic risk factor; genetic variant; high risk; in utero; insight; meetings; migration; mouse model; novel; offspring; programs; public health relevance; receptor; social; trait

DESCRIPTION (provided by applicant): Birth defects in human populations occur with an approximate frequency of 3 percent of all live births, often as a result of unknown or poorly understood causes. The long-term goal of our research is to understand the mechanisms of fetal development and the genesis of birth defects. Towards this goal, we have used genetically modified mice to study embryonic eyelid closure, an essential morphogenetic event of the mammalian eye. This event, involving epithelial cell migration that leads to fusion of the upper and lower eyelids, is a significant model for fundamental developmental processes, such as palate fusion and neural tube closure, whereby an opening in the epithelium is closed by morphogenetic forces. Our studies have shown that embryonic eyelid closure is a developmental threshold trait regulated by an exceptionally complex genetic network; diverse lesions that disrupt the network will result in failure to meet the threshold and consequently cause a defect in ontogenesis. We have identified MAP3 kinase 1 (MAP3K1) as an integral component of this network. Eyelid closure depends on Map3k1 as the major genetic locus and a series of "weaker" alleles with graded strength. Although unveiling the genetic contribution to eyelid closure is the subject of extensive research, the environmental factors that may shift the threshold, and the genetic variations that may determine sensitivity to a particular environmental agent, are largely unknown. This R21 exploratory proposal will test the idea that eyelid closure is a multifactorial developmental threshold depending on complex interactions of genetic and environmental factors. We will use Map3k1 as a model gene and dioxin as a model compound to test the hypothesis supported by preliminary data that allelic Map3k1 deletion is a genetic risk factor that predisposes environmental insults for congenital eye disorders. In three Specific Aims, we will use genetic mutant mice to evaluate whether Map3k1 allelic deletion increases susceptibility to eyelid defects by in utero dioxin exposure; in the exposed fetuses, we will investigate the gene-environment interaction mechanisms that lead to eyelid developmental defects; we will use compound genetic mutant mice to assess whether dioxin acts through the Ah receptor-MAP3K1 axis to affect eyelid morphogenesis. If successful, we will establish an experimental paradigm to study gene-environment interaction mechanisms underlying multifactorial birth defects and chart a path to test for these connections of many other genetic and environmental risk factors. Furthermore, we will expand our understanding on the mechanisms of genetic susceptibility to dioxin induced birth defects. This information will help to direct epidemiology and risk assessment efforts towards a subgroup of susceptible individuals with pre-existing genetic conditions. In addition, unraveling the mechanisms of gene- environment interaction will have significant public health benefits, because it provides an avenue for using genetic information to stratify the allocation of environmental intervention for disease prevention.

描述（由申请人提供）：人类出生缺陷的发生频率约为所有活产婴儿的3%，通常是由于未知或了解不多的原因。我们研究的长期目标是了解胎儿发育的机制和出生缺陷的发生。为了实现这一目标，我们使用转基因小鼠来研究胚胎眼睑闭合，这是哺乳动物眼睛的基本形态发生事件。该事件涉及导致上眼睑和下眼睑融合的上皮细胞迁移，是基本发育过程的重要模型，例如腭融合和神经管闭合，其中上皮中的开口通过形态发生力闭合。我们的研究表明，胚胎眼睑闭合是一个由异常复杂的遗传网络调节的发育阈值特征;破坏网络的各种病变将导致无法达到阈值，从而导致个体发育缺陷。我们已经确定MAP 3激酶1（MAP 3 K1）是该网络的一个组成部分。眼睑闭合依赖于Map 3 k1作为主要的遗传位点和一系列具有分级强度的“较弱”等位基因。虽然揭开眼睑闭合的遗传贡献是广泛研究的主题，但可能改变阈值的环境因素以及可能决定对特定环境因子敏感性的遗传变异在很大程度上是未知的。这个R21探索性提案将测试眼睑闭合是一个多因素发育阈值的想法，取决于遗传和环境因素的复杂相互作用。我们将使用Map 3 k1作为模型基因，二恶英作为模型化合物来检验由初步数据支持的假设，即等位基因Map 3 k1缺失是一种遗传风险 这是先天性眼病的环境因素。在三个特定目标中，我们将使用遗传突变小鼠来评估Map 3 k1等位基因缺失是否增加宫内二恶英暴露对眼睑缺陷的易感性;在暴露的胎儿中，我们将研究导致眼睑发育缺陷的基因-环境相互作用机制;我们将使用复合遗传突变小鼠来评估二恶英是否通过Ah受体-MAP 3 K1轴影响眼睑形态发生。如果成功，我们将建立一个实验范式来研究多因素出生缺陷背后的基因-环境相互作用机制，并绘制一条路径来测试许多其他遗传和环境风险因素的这些联系。此外，我们将扩大我们的理解的遗传易感性的二恶英导致的出生缺陷的机制。这些信息将有助于 直接针对具有预先存在的遗传条件的易感个体亚组开展流行病学和风险评估工作。此外，揭示基因-环境相互作用的机制将对公共卫生产生重大益处，因为它为利用遗传信息对疾病预防的环境干预进行分层分配提供了一条途径。