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Toxicogenomics of metal response in genetically-variable Drosophilapopulations

遗传变异果蝇种群中金属反应的毒理学

基本信息

批准号：
10088445
负责人：
Stuart John Macdonald
金额：
$ 20.45万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
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：
2019-02-01 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10088445
关键词：
ATAC-seq Alleles Animals Biological Biological Assay Biological Models Biological Process Brain Cadmium Cell physiology Child Chromatin Complex Data Data Set Development Diet Dissection Dose Drosophila genus Drug Metabolic Detoxication Elements Environment Enzymes Epigenetic Process Ethics Exposure to Food Gene Expression Genes Genetic Genetic Models Genetic Polymorphism Genetic Predisposition to Disease Genetic Transcription Genetic Variation Genome Genomics Genotype Head Health Human Inbreeding Individual Industrialization Laboratories Lead Mammals Manganese Maps Measures Mercury Metal exposure Metals Methylmercury Compounds Minor Modeling Molecular Nature Neurologic Neurons Nucleic Acid Regulatory Sequences Paint Parkinson Disease Pathway interactions Pharmacologic Substance Phenotype Physiological Poison Population Population Study Predisposition Quantitative Trait Loci Recombinants Recording of previous events Resolution Resources Risk Role Series Soil Syndrome System Testing Tissues Toxic Environmental Substances Toxic effect Toxicogenomics Toxin Transposase Uncertainty Variant Work associated symptom base brain tissue cognitive development cognitive function contaminated drinking water dietary experimental study exposed human population feeding fly genetic approach genome-wide insight lead exposure metal poisoning neurotoxicity phenotypic data response toxic metal trait transcriptome sequencing

项目摘要

PROJECT SUMMARY Environmental toxins present considerable risk to human health, and among the most concerning are toxic metals. Due to broad industrial use and historically widespread incorporation into common products (e.g., paints), there is widespread metal contamination of drinking water, food items, and soil. Even extremely low levels of exposure to certain metals can have deleterious consequences for human health. This is especially true for children since metal exposure has been associated with poorer cognitive function and neurological problems. Given the major health risks associated with metal toxicity it is critical to understand the genetic, epigenetic, and molecular pathways underlying the response to toxic metals. It is clear there is considerable variation among individuals in how they respond to a given toxic compound, whether it is an environmental metal toxin such as lead, or a pharmaceutical compound such as a chemotherapeutic. For some individuals a particular dose can be highly damaging, while for others that same dose has a much more minor effect. Understanding the nature of differential response to a toxic metal challenge, and finding genes that contribute to variation in susceptibility to metal toxicity, will enable us to more accurately predict the risks associated with exposure, better understand the symptoms associated with metal toxicity, and more specifically treat exposed individuals. A principal challenge with exploring genetic variation for metal toxicity response directly in humans is the extreme toxicity of the metals, precluding ethical human studies, and the lack of control of toxin dose in any population-based study. Considerable advantages are offered by model laboratory systems such as Drosophila (fruitflies); Exposure levels can be precisely controlled, tissue-specific measures of gene expression can be gathered, and candidate toxicity genes can be functionally validated using a sophisticated genetic toolkit. Critically, there is broad conservation between humans and flies, including many genes involved in brain development and neuronal function, and many known metal response and detoxification genes. Thus, studies in flies can provide fundamental insight into toxicity variation in human populations. In this proposal we will exploit a very large, genetically well-characterized panel of Drosophila inbred lines. We will integrate data from powerful, efficient toxicity screens, and from a series of sophisticated genomics studies that generate genomewide gene expression measures and maps of regulatory regions. As a result, we will identify mechanisms and genes contributing to variation in toxicity to four key environmental and industrial metal toxins; lead, mercury, cadmium, and manganese.

项目总结