Neuro-Immune Mechanisms in Early Life Stress-Induced Gastrointestinal Disease

项目总结 在产前和出生后发育的关键时期暴露于早期生活逆境(ELA)是一种 高发胃肠道(GI)疾病，包括应激性疾病的晚年发病的重要危险因素 肠综合征(IBS)和炎症性肠病(IBD)。ELA和GI之间的精确联系机制 疾病易感性尚不清楚，因此缺乏管理和治疗目标和生物标记物。 我们使用猪模型进行的研究表明，ELA改变了胃肠道发育的正常过程，从而 在终生肠道屏障功能障碍或“肠漏”，神经免疫失调和增加的胃肠道疾病 概述了人类应激相关胃肠道疾病的大部分病理生理学和临床特征。我们 最近发现了两个与ELA诱导的成年期胃肠道疾病易感性和严重性相关的因素： (1)肠道肥大细胞过度活动增强且持续；(2)与雌性生物交配增加 风险和雄性受到保护。此外，我们还发现了肥大细胞表型的新的性别差异。 雌性动物肥大细胞表现出增强的合成存储和应激诱导的介质释放 如组胺、蛋白酶和5-羟色胺，它们在胃肠道神经免疫疾病中具有已知的作用。我们的 假设肥大细胞和生物性相互作用，以组织胃肠道屏障的发展和 神经免疫系统，因此决定了暴露于ELA后的终生疾病风险。我们 为实现这一目标设计了三个具体目标。目标1将检验过度激活的假设 在出生后早期发育的胃肠道肥大细胞导致胃肠道屏障和成年后的神经免疫功能障碍。 目标2将检验这一假设，即女性对ELA诱导的胃肠道疾病的易感性增加取决于 雄激素在早期发育过程中的作用。目标3将检验ELA和围产期雄激素的假设 通过表观遗传和转录机制编程肥大细胞，导致肥大细胞过度活跃，从而 导致胃肠道屏障和神经免疫功能障碍进入成年期。总而言之，拨款中建议的研究 预计应用将导致对ELA诱导的和ELA诱导的 性别偏向的胃肠道神经免疫性疾病最终可能揭开保护胃肠道的新治疗靶点 在脆弱的应激期，并在治疗上调整男女成人疾病的系统。

PROJECT SUMMARY Exposure to early life adversity (ELA) during critical periods of prenatal and postnatal development is an important risk factor for the later life onset of highly prevalent gastrointestinal (GI) diseases, including irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). The precise mechanisms linking ELA and GI disease susceptibility are unknown and thus management and therapeutic targets and biomarkers are lacking. Our studies using a porcine model demonstrated that ELA alters the normal course of GI development resulting in lifelong intestinal barrier dysfunction or “leaky gut', neuroimmune dysregulation and increased GI disease that recapitulates much of the pathophysiology and clinical features of human stress-related GI disorders. We recently identified two factors associated with ELA-induced GI disease susceptibility and severity in adulthood: (1) heightened and persistent intestinal mast cell hyper-activity and (2) biological sex with females at increased risk and males protected. Furthermore, we have identified novel sex-differences in the mast cell phenotype in that mast cell from female animals exhibit enhanced synthesis storage and stress-induced release of mediators such as histamine, proteases and serotonin which have known roles in GI neuroimmune disorders. Our hypothesis is that mast cells and biological sex interact to organize the development of GI barrier and neuroimmune systems, consequently determining the lifetime risk to disease following exposure to ELA. We have designed three specific aims to accomplish this objective. Aim 1 will test the hypothesis that hyper-activation of GI mast cells during early postnatal development lead to GI barrier and neuroimmune dysfunction in adulthood. Aim 2 will test the hypothesis that the heightened vulnerability of females to ELA-induced GI disease depends on androgens acting during early development. Aim 3 will test the hypothesis that ELA and perinatal androgens program mast cells, via epigenetic and transcriptional mechanisms, resulting in mast cell hyperactivity which drives GI barrier and neuroimmune dysfunction into adulthood. Together, the studies proposed in the grant application are expected to result in a major paradigm shift in the understanding the origins of ELA-induced and sex-biased GI neuroimmune diseases which could ultimately unveil new therapeutic targets to protect the GI system during vulnerable periods of stress and to therapeutically modulate adult diseases in both sexes.