Genetics of epigenetic response to high circulating glucocorticoids and organophosphorus compounds

高循环糖皮质激素和有机磷化合物的表观遗传反应的遗传学

• 批准号: 10553694
• 负责人: BYRON C JONES
• 金额: $ 58.08万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553694
• 关键词: Acetylcholinesterase Inhibitors; Acute; Age Months; Animal Model; Animals; Bayesian Network; Bioinformatics; Biological; Biological Markers; Candidate Disease Gene; Combined Modality Therapy; Complex; Control Locus; Corticosterone; Cytokine Gene; DNA Methylation; Data; Diagnosis; Disease; Dissection; Endocrinology; Environment; Epigenetic Process; Etiology; Euthanasia; Exposure to; Family; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Variation; Genome; Genotype; Glucocorticoids; Goals; Gulf War; Hippocampus; Human; Inbred Mouse; Inbred Strains Mice; Inbreeding; Individual; Individual Differences; Inflammatory; Link; Long-Term Effects; Malaise; Maps; Measures; Mediating; Methylation; Modeling; Molecular; Mouse Strains; Mus; Names; Neurologic; Organophosphorus Compounds; Pathway Analysis; Pathway interactions; Persian Gulf; Persian Gulf Syndrome; Phenotype; Physiological; Population; Predisposition; Prefrontal Cortex; Proteome; Quantitative Trait Loci; Recombinants; Research; Resources; Stress; Symptoms; System; Update; Variant; Work; animal data; design; fluorophosphate; gastrointestinal; gene environment interaction; gene network; genetic analysis; genomic locus; histone modification; insertion/deletion mutation; learning network; mouse model; novel; phenome; respiratory; response; transcriptome; treatment response

The USA sent approximately 700,000 troops to the Persian Gulf to participate in the 1990-91 Gulf War. Of those who returned, 25-30% complained of a generalized malaise with gastrointestinal, endocrinological, respiratory and neurological complaints, which was named Gulf War Illness (GWI). Many of those returning with GWI are still sick nearly 30 years after their exposure, with no cure. What changes allow these symptoms to persist over many years? Genetic variation among the troops may have caused them to respond differently to the exposure. Epigenetic alterations in gene regulation are the most likely candidate for the persistence of symptoms. We and others have developed an exposure regime in mice that mimics both troop exposures and biological effects of GWI. This model uses corticosterone pretreatment (CORT; to simulate physiological stress) combined with an irreversible acetylcholinesterase inhibitor, diisopropyl fluorophosphate (DFP); as troops were exposed to many acetylcholinesterase inhibitors. Initial studies showed acute changes in proinflammatory cytokine genes and changes in methylation of genes following exposure to CORT combined with DFP. PI Jones and colleagues have seen significant differences in proinflammatory gene expression response to the treatment among more than 25 different genotypes (i.e., inbred mouse strains) and have been able to map quantitative trait loci which mediate this effect. The proposed research takes the next step to understand the genetics of epigenetic changes related to the persistence of GWI.

美国向波斯湾派遣了大约70万军队， 1990-91年海湾战争。在那些返回的人中，25-30%的人抱怨说， 胃肠道、内分泌、呼吸和神经系统不适 这种疾病被称为海湾战争病（GWI）。很多人回来的时候 GWI在暴露近30年后仍然患病，无法治愈。哪些变化 让这些症状持续多年的遗传变异 部队可能导致他们对暴露的反应不同。后生 基因调控的改变是最有可能的候选人的持久性， 症状我们和其他人已经在小鼠身上开发了一种暴露机制， 部队暴露和GWI的生物效应。这个模型使用皮质酮 预处理（CORT;模拟生理应激）结合不可逆 乙酰胆碱酯酶抑制剂，氟磷酸二异丙酯（DFP）;作为部队 暴露于许多乙酰胆碱酯酶抑制剂。初步研究显示，急性 促炎细胞因子基因的变化和基因甲基化的变化 在暴露于CORT与DFP组合之后。PI Jones及其同事 在促炎基因表达反应中， 在超过25种不同基因型之间进行处理（即，近交系小鼠品系）和 已经能够绘制介导这种效应的数量性状基因座。拟议 研究人员下一步要了解表观遗传变化的遗传学 与GWI的持续性有关。