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Gene-Environment Interactions Causing Differential Susceptibility to Chemical Exposure in High-Throughput Screening

基因-环境相互作用导致高通量筛选中对化学品暴露的敏感性差异

基本信息

批准号：
9925513
负责人：
David M Reif
金额：
$ 22.5万
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：
2019
资助国家：
美国
起止时间：
2019-06-15 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9925513
关键词：
Address Affect Animal Model Behavior Behavioral Behavioral Assay Bioinformatics Biological Biological Assay Chemical Exposure Chemicals Conflict (Psychology)Congenital Abnormality Data Development Developmental Process Embryo Environment Environmental Exposure Environmental Health Equation Exhibits Exposure to Fertility Fertilization Genetic Genetic Predisposition to Disease Genetic Variation Genome Genomic Segment Health Health Hazards Heterogeneity Human Impaired cognition In Vitro Incidence Individual Industrialization Informatics Link Malignant Neoplasms Measures Metals Methods Morphology Neurodegenerative Disorders Outcome Paint Pattern Pesticides Phenotype Play Population Predisposition Process Public Health Risk Role Sequence Analysis Solid Source Speed System Technology Testing Time Zebrafish adverse outcome cognitive development critical period environmental agent environmental chemical environmental chemical exposure experimental study flexibility gene environment interaction high throughput screening in vitro Assay in vivo individual response individual variation nanomaterials response screening stressor

项目摘要

ABSTRACT Exposure to environmental chemicals has been linked to increases in cancer incidence, birth defects, impaired cognitive development, and neurodegenerative disease. Unfortunately, the gap between the ever-expanding number of chemicals in the environment and data on their potential health hazards continues to widen. Although recent advancements that use in vitro, high-throughput screening (HTS) technologies may speed the pace of chemical testing, those platforms cannot detect adverse health effects diagnosable only at a systemic level, such as abnormal development or aberrant behavior. Additionally, an in vivo context is needed to quantify the contribution of interindividual genetic variation to susceptibility differences in developmental or behavioral consequences of exposure. There is strong evidence that gene-environment interactions (GxE) related to individual genetic variation play an important role in health outcomes, and that these interactions are likely a major source of the heterogeneity in response to chemical exposure. Thus, understanding the role of GxE in differential susceptibility to chemical exposure will be key to protecting public health. We propose development of a collaborative bioinformatic + experimental system to study health outcomes affected by gene-environment interactions (Y=GxE) that comprehensively describes (Y), refines characterization of (E), then investigates and probes (G). This system will leverage massive data generated by HTS of chemicals through morphological and behavioral assays in embryonic zebrafish during the critical period (the first 5 days immediately after fertilization) when developmental processes are most highly-conserved between this vertebrate model organism and humans. These data will be analyzed to quantify GxE that elicit differential health outcomes following chemical exposure. The lasting significance of this proposal will be a scalable, efficient system to rapidly address questions of differential genetic susceptibility to an expanding chemical universe.

摘要