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

项目摘要 在产前和产后发育的关键时期暴露于早期生活逆境（ELA）是一种 高流行性胃肠道（GI）疾病，包括易激惹性疾病， 肠综合征（IBS）和炎性肠病（IBD）。连接ELA和GI的精确机制 疾病易感性是未知的，因此缺乏管理和治疗靶点和生物标志物。 我们使用猪模型的研究表明，ELA改变了胃肠道发育的正常过程， 在终身肠屏障功能障碍或"肠漏"、神经免疫失调和增加的GI疾病中， 概括了人类应激相关GI疾病的许多病理生理学和临床特征。我们 最近确定了两个与成人中ELA诱导的GI疾病易感性和严重性相关的因素： (1)升高和持续的肠肥大细胞过度活跃，以及（2）在升高时雌性动物的生物学性别 风险和男性保护。此外，我们已经确定了肥大细胞表型的新的性别差异， 来自雌性动物肥大细胞表现出增强的介质合成储存和应激诱导的介质释放 例如组胺、蛋白酶和血清素，它们在GI神经免疫紊乱中具有已知的作用。我们 假设肥大细胞和生物性别相互作用组织GI屏障发育， 神经免疫系统，从而确定暴露于ELA后的终身疾病风险。我们 为实现这一目标，我们制定了三个具体目标。目标1将检验超激活 胃肠道肥大细胞在出生后早期发育过程中的大量减少导致成年期胃肠道屏障和神经免疫功能障碍。 目的2将检验这一假设，即女性对ELA诱导的GI疾病的易感性增加取决于 在早期发育过程中作用的雄激素。目的3将检验ELA和围产期雄激素 通过表观遗传和转录机制对肥大细胞进行编程，导致肥大细胞过度活跃， 导致成年期胃肠道屏障和神经免疫功能障碍。总的来说， 应用预计将导致一个重大的范式转变，在理解的起源ELA诱导， 性别偏见的胃肠道神经免疫疾病，最终可能揭示新的治疗目标，以保护胃肠道 在脆弱时期的压力和治疗调节成人疾病的两性系统。

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.