Comparative toxicogenomics to determine conserved genetic and environmental interactions in craniofacial birth defects

比较毒物基因组学以确定颅面出生缺陷中保守的遗传和环境相互作用

• 批准号: 10664324
• 负责人: Joshua L Everson
• 金额: $ 10.55万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-07 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664324
• 关键词: Affect; Alcohols; Animals; Bioinformatics; Biological Models; Brain; CRISPR/Cas technology; Chemicals; Communication; Congenital Abnormality; Craniofacial Abnormalities; Critical Pathways; DNA Sequence Alteration; Data; Defect; Development; Disease; Dizziness; Dysmorphology; Embryo; Environment; Environmental Exposure; Environmental Risk Factor; Erinaceidae; Ethanol; Etiology; Face; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Genetic Variation; Growth; Head; Human; Logic; Modeling; Modernization; Molecular; Morphogenesis; Mus; Mutation; Nature; Palate; Pathway interactions; Prevention; Process; Reader; Risk; SHH gene; Signal Pathway; Signal Transduction; Sonic Hedgehog Pathway; Testing; Toxic Environmental Substances; Toxic effect; Toxicogenomics; Validation; Zebrafish; alcohol response; comparative; craniofacial; craniofacial development; developmental toxicology; environmental chemical; gene environment interaction; gene network; gene regulatory network; genetic risk factor; high throughput analysis; human disease; insight; novel; prevent; smoothened signaling pathway; teratogenesis; toxicant; transcriptome; transcriptomics

Project Summary Craniofacial dysmorphologies are among the most common human birth defects. The multifactorial basis of human birth defects has hindered identification of culpable genes and toxicants. Environmental exposures occur in mixtures, and genetic variation can sensitize embryos to these mixtures. This proposal uses bioinformatics and high-throughput analyses to predict and characterize multifactorial interactions in birth defects using zebrafish and mice. The aims of this proposal are: (1) Define synergistic interactions between environmental toxicants; (2) Model and characterize gene-environment interactions; (3) Test human disease relevance and evolutionary conservation. This approach leverages my expertise in zebrafish and mouse developmental toxicology to rapidly and efficiently gain insights into the most important unanswered questions surrounding birth defect etiology. The studies proposed will provide a direct avenue for prevention through risk communication of novel environmental and genetic risk factors.

项目摘要 颅面畸形是人类最常见的出生缺陷之一。的多因素基础 人类出生缺陷阻碍了对有罪基因和有毒物质的鉴定。环境暴露 在混合物中发生，遗传变异可以使胚胎对这些混合物敏感。该提案使用 生物信息学和高通量分析，以预测和表征出生中的多因素相互作用 用斑马鱼和老鼠做实验。本建议的目的是：（1）确定以下方面的协同互动： 环境毒物;（2）模拟和表征基因-环境相互作用;（3）测试人类疾病 相关性和进化保守性。这种方法利用了我在斑马鱼和老鼠方面的专业知识 发展毒理学，以快速，有效地了解最重要的悬而未决的问题 出生缺陷的病因学。拟议的研究将提供一个通过风险进行预防的直接途径 传播新的环境和遗传风险因素。