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.

项目概要 颅面畸形是最常见的人类出生缺陷之一。多因素基础 人类出生缺陷阻碍了罪魁祸首和有毒物质的识别。环境暴露 存在于混合物中，遗传变异可以使胚胎对这些混合物敏感。本提案使用 生物信息学和高通量分析来预测和表征出生时的多因素相互作用 使用斑马鱼和小鼠的缺陷。该提案的目标是： (1) 定义之间的协同相互作用 环境毒物； (2) 对基因-环境相互作用进行建模和表征； (3)测试人体疾病 相关性和进化保护。这种方法利用了我在斑马鱼和小鼠方面的专业知识 发育毒理学可快速有效地深入了解最重要的未解答问题 周围出生缺陷的病因学。拟议的研究将为通过风险进行预防提供直接途径 新的环境和遗传风险因素的交流。