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

生命早期压力诱发的胃肠道疾病的神经免疫机制

基本信息

批准号：
10413828
负责人：
Adam Moeser
金额：
$ 44.56万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10413828
关键词：
Abdominal Pain Adult Agriculture Androgens Animals Applications Grants Automobile Driving Biogenesis Biological Biology Cell Degranulation Cellular biology Chronic Clinical Cytoplasmic Granules Development Disease Disease susceptibility Economics Elderly Engraftment Epigenetic Process Exhibits Exposure to Family suidae Female Food Hypersensitivity Functional disorder Future Gastrointestinal Diseases Gastrointestinal Physiology Genetic Transcription Goals Gonadal Steroid Hormones Histamine Human Hyperactivity Immune Immune System Diseases Immune signaling Immune system Industry Inflammatory Bowel Diseases Intestines Irritable Bowel Syndrome Knowledge Lead Leaky Gut Life Link Longevity Mediator of activation protein Morbidity - disease rate Mus Neuroimmune Neuroimmune system Neuroimmunomodulation Patients Peptide Hydrolases Perinatal Persons Phenotype Plague Play Practice Management Predisposition Prevalence Prevention Production Public Health Research Risk Risk Factors Role Serotonin Severity of illness Sex Bias Sex Differences Shapes Stress Testing Therapeutic Therapeutic Intervention Tissues Weaning abuse neglect biological sex cell motility critical period design disorder risk early life adversity early life stress experience gastrointestinal gastrointestinal system inhibitor intestinal barrier lifetime risk male mast cell mature animal mortality neonate neuroinflammation new technology new therapeutic target novel novel therapeutics porcine model postnatal development prenatal programs resilience sex sex development disorder sexual dimorphism stem cells targeted biomarker therapeutic target

项目摘要

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.

项目概要在产前和产后发育的关键时期暴露于生命早期逆境（ELA）是一种晚年发病高度流行的胃肠道 (GI) 疾病（包括易激惹）的重要危险因素肠综合征 (IBS) 和炎症性肠病 (IBD) 连接 ELA 和 GI 的精确机制。疾病易感性尚不清楚，因此缺乏管理和治疗靶点以及生物标志物。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，从而导致终生肠道屏障功能障碍或“肠漏”、神经免疫失调和胃肠道疾病增加概括了人类压力相关胃肠道疾病的大部分病理生理学和临床特征。最近确定了与 ELA 诱发的成年期胃肠道疾病易感性和严重程度相关的两个因素： (1) 呼吸和持续的肠道肥大细胞过度活跃以及 (2) 与雌性的生物性别增加此外，我们还发现了肥大细胞表型的新性别差异。来自雌性动物的肥大细胞表现出增强的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，它们在胃肠道神经免疫性疾病中具有已知的作用。假设是肥大细胞和生物性别相互作用来组织胃肠道屏障的发展和神经免疫系统，从而确定接触 ELA 后终生患病的风险。设计了三个具体目标来实现这一目标，目标 1 将检验过度激活的假设。出生后早期发育期间胃肠道肥大细胞的减少导致成年期胃肠道屏障和神经免疫功能障碍。目标 2 将检验以下假设：女性哮喘对 ELA 诱发的胃肠道疾病的脆弱性取决于目标 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对肥大细胞进行编程，导致肥大细胞过度活跃资助中提出的研究共同推动了成年期的胃肠道屏障和神经免疫功能障碍。预计应用程序将导致理解 ELA 诱导和起源的重大范式转变。性别偏见的胃肠道神经免疫疾病最终可能会揭示保护胃肠道的新治疗靶点系统在压力脆弱时期并治疗调节两性的成人疾病。