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：
10117477
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/10117477
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.

美国派出约70万军队前往波斯湾参加 1990-91 海湾战争。在返回的人中，25-30% 抱怨普遍存在胃肠道、内分泌、呼吸和神经系统不适投诉，被命名为海湾战争疾病（GWI）。许多回国的人都带着 GWI 在接触病毒近 30 年后仍然患病，且无法治愈。有什么变化让这些症状持续多年？之间的遗传变异部队可能导致他们对暴露的反应不同。表观遗传基因调控的改变是最有可能持久存在的候选者症状。我们和其他人已经在小鼠身上开发了一种模仿的暴露制度部队暴露情况和 GWI 的生物效应。该模型使用皮质酮预处理（CORT；模拟生理应激）与不可逆的乙酰胆碱酯酶抑制剂，氟磷酸二异丙酯（DFP）；就像部队一样接触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 与 DFP 结合后。 PI Jones 和他的同事们发现促炎基因表达反应存在显着差异超过 25 种不同基因型（即近交系小鼠品系）之间的治疗以及已经能够绘制介导这种效应的数量性状基因座。拟议的研究进一步了解表观遗传变化的遗传学与 GWI 的持续存在有关。