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Characterizing Gene-Environment Interactions that Affect Individual Susceptibility to an Expanding Chemical Exposome

表征影响个体对不断扩大的化学暴露体的敏感性的基因-环境相互作用

基本信息

批准号：
10522232
负责人：
Fred A. Wright
金额：
$ 43.65万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-08 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522232
关键词：
Address Affect Animal Model Behavior Behavioral Bioinformatics Biological Biological Assay Birth Candidate Disease Gene Chemical Exposure Chemicals Data Defect Development Developmental Process Disease susceptibility Embryo Environment Environmental Exposure Environmental Health Equation Exposure to Fertility Fertilization Genetic Genetic Predisposition to Disease Genetic Variation Genome Genomic Segment Health Health Hazards Heritability Human Impaired cognition Incidence Individual Informatics Link Malignant Neoplasms Measures Methods Morphology Neurodegenerative Disorders Outcome Paint Pattern Phenotype Play Population Population Heterogeneity Predisposition Process Public Health Reproducibility Research Risk Role Sequence Analysis Signal Transduction Solid Speed Susceptibility Gene System Technology Testing Time Variant Vulnerable Populations Zebrafish base behavioral phenotyping cognitive development environmental chemical environmental chemical exposure experimental study gene environment interaction high throughput screening in vitro Assay individual response inter-individual variation novel novel strategies response screening stem

项目摘要

ABSTRACT Environmental chemical exposure has been linked to increases in cancer incidence, birth and developmental defects, impaired cognitive development, and neurodegenerative disease. However, even as the number of manufactured chemicals in the environment grows into the hundreds-of-thousands, comprehensive data on the human and environmental health hazards remain sparse to nonexistent. The data are especially sparse regarding questions of differential susceptibility, where gene-environment interaction (GxE) effects stemming from individual genetic variation play an important role in health outcomes. Thus, understanding the role of GxE in differential susceptibility to an expanding chemical exposome is key to protecting public health— particularly that of vulnerable populations. We propose a solution that combines novel analytics with the power of new high-throughput screening technologies to detect GxE underlying differential susceptibility in a diverse population of zebrafish. Our three Specific Aims will (1) Identify environmental chemicals that induce the greatest differences in population disease susceptibility; (2) Identify critical exposure concentrations and confirm genetic heritability of population susceptibility differences; and (3) Identify and experimentally validate genomic regions associated with differential susceptibility to chemical exposure. The immediate impact of this proposal will be novel empirical evidence for the role of GxE in differential population susceptibility. The lasting significance of this proposal will be a scalable, sustainable system to rapidly address questions of differential genetic susceptibility to an expanding chemical exposome. The data-driven, bioinformatic approaches developed here will be extensible to other systems for identifying patterns of phenotypic variation suggesting GxE.

摘要环境化学品暴露与癌症发病率、出生和发育的增加有关。缺陷、认知发育受损和神经退行性疾病。然而，即使数量环境中的制造化学品增长到成千上万，全面的数据，对人类和环境健康危害仍然很少甚至不存在。数据特别稀少关于不同的易感性问题，其中基因-环境相互作用（GxE）的影响源于个体遗传变异对健康结果起着重要作用。因此，了解 GxE对不断扩大的化学物质的敏感性是保护公众健康的关键- 特别是弱势群体。我们提出了一种解决方案，将新颖的分析与强大的新的高通量筛选技术，以检测GxE潜在的差异敏感性在不同的斑马鱼的种群我们的三个具体目标是：（1）确定环境化学品，（2）确定关键接触浓度，确认群体易感性差异的遗传性;（3）识别和实验验证与化学暴露的不同易感性相关的基因组区域。这件事的直接影响是该提案将是GxE在不同人群易感性中的作用的新的经验证据。持久这一建议的意义将是一个可扩展的，可持续的系统，以迅速解决差异化的问题，对不断扩大的化学物质的遗传易感性。数据驱动的生物信息学方法这里开发的将可扩展到其他系统，用于识别表型变异的模式， GxE