Genetic and epigenetic regulation of the stress response and implications for ruminant health

糖皮质激素(GC)有助于在微生物感染期间维持生理平衡，部分是通过调节炎症和免疫反应。循环中的GC水平受到免疫系统和下丘脑-垂体-肾上腺(HPA)轴信号的严格调控。据推测，这些双向交流通路的中断或功能障碍可能导致家畜炎症性疾病的发病，遗传学以及母体应激诱导的胎儿表观遗传编程影响疾病的易感性和预后。本课题组优化了一个急性细菌内毒素炎症应激(BEIS)模型来研究绵羊在模拟细菌感染过程中的HPA反应，并利用该应激模型研究了应激反应的遗传学和表观遗传学及其与宿主免疫反应(IR)和行为的关系。在这一轮更新中，我们建议：1)精细定位以前在全基因组关联研究中确定的BEIS高(HCR)和低(LCR)皮质醇反应绵羊的遗传关联；2)评估HCR和LCR母羊的哺乳行为和羔羊第一次喂食的时间作为羔羊健康潜力的指标；3)使用各种感染模式确定HPA反应和粘膜免疫之间的关联；4)确定在胎儿发育过程中受BEIS编程影响的基因通路；以及5)使用各种感染模型评估BEIS编程下的后代的粘膜免疫。基因的鉴定、基因的多态性以及对胚胎发育过程中基因与环境相互作用的深入了解将有助于改善动物健康和食品质量，减少农业中对抗生素的依赖，并增强我们对哺乳动物神经内分泌免疫系统调节途径的了解。

Glucocorticoids (GC) help to maintain physiological homeostasis during microbial infections, in part, by regulating the inflammatory and immune response. Circulating GC levels are tightly regulated by signals from both the immune system and hypothalamic-pituitary-adrenal (HPA) axis. It is suspected that disruption of these bi-directional communication pathways, or their dysfunction, may contribute to the pathogenesis of inflammatory diseases in livestock, and that genetics as well as maternal stress-induced epigenetic programming of the fetus influence disease susceptibility and outcome. Our group has optimized an acute bacterial endotoxin inflammatory stress (BEIS) model to study the ovine HPA response during simulated bacterial infection, and we have used this stress model to study the genetics and epigenetics of the stress response and it's relationship with the host immune response (IR) as well as behaviour. In this round of renewal, we are proposing to; 1) fine map genetic associations that were previously identified with BEIS-ranked high (HCR) and low (LCR) cortisol responding sheep in a genome-wide association study, 2) assess HCR and LCR ewe nursing behaviour and time to lamb's first feeding as indicators of lamb health potential, 3) identify associations between HPA responsiveness and mucosal immunity using various infection models, 4) identify gene pathways that are subject to BEIS programming during fetal development, and 5) assess mucosal immunity of offspring subjected to BEIS programming using various infection models. It is anticipated that the identification of genes, gene polymorphisms, and enhanced understanding of gene-by-environment interaction during fetal development will contribute to improving animal health and food quality, reducing our dependence on antibiotics in agriculture, and enhance our understanding of the pathways that regulate the neuroendocrine-immune system in mammalians.