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

基本信息

批准号：
10379235
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
项目类别：
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/10379235
关键词：
Acetylcholinesterase Inhibitors Acute Age-Months Animal Model Animals Bayesian Network Bioinformatics Biological Biological Markers Candidate Disease Gene Complex Control Locus Corticosterone Cytokine Gene DNA Methylation Data Diagnosis Disease Dissection Environment Epigenetic Process Etiology Exposure to Family Gene Expression Gene Expression Regulation Genes Genetic Genetic Variation Genome Genotype Glucocorticoids Goals Gulf War Hippocampus (Brain)Human Inbred Mouse Inbred Strains Mice Inbreeding Individual Individual Differences 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 QTL Genes Quantitative Trait Loci Recombinants Research Resources Stress Symptoms System Update Variant Work animal data base design fluorophosphate gastrointestinal gene environment interaction genetic analysis genomic locus histone modification insertion/deletion mutation learning network mouse model novel phenome respiratory response transcriptome treatment response

项目摘要

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.

美国派遣大约70万部队前往波斯湾参加 1990 - 91年海湾战争。在返回的人中，有25-30％的人抱怨胃肠道不适，内分泌，呼吸和神经学投诉，被称为海湾战争疾病（GWI）。许多返回的人 GWI在接触近30年后仍然生病，无法治愈。什么变化让这些症状持续多年？遗传变异部队可能导致他们对暴露的反应不同。表观遗传学基因调节的改变是持续存在的最有可能的候选者症状。我们和其他人在小鼠中建立了一种模仿的曝光状态部队的暴露和GWI的生物效应。该模型使用皮质酮预处理（Cort；用于模拟生理压力）与不可逆的乙酰胆碱酯酶抑制剂，二异丙磷酸二异丙磷酸酯（DFP）；作为部队暴露于许多乙酰胆碱酯酶抑制剂。初步研究表明急性促炎细胞因子基因的变化和基因甲基化的变化暴露于Cort之后，与DFP结合。 Pi Jones及其同事有发现促炎基因表达反应的显着差异 25种以上不同的基因型（即，近交小鼠菌株）和能够绘制介导这种效果的定量性状基因座。提议研究采取下一步了解表观遗传变化的遗传学与GWI的持久性有关。