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

• 批准号: 8548538
• 负责人: Adam Moeser
• 金额: $ 31.44万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8548538
• 关键词: Abdominal Pain; Acetylcholine; Adult; Affect; Agriculture; Animal Model; Animals; Antigens; Biological; Biological Assay; Biological Models; Cell Culture System; Chronic; Clinical; Data; Defect; Development; Diarrhea; Disease; Disease Resistance; Elderly; Enteral; Epithelial; Event; Family suidae; Food Hypersensitivity; Functional disorder; Gastrointestinal Diseases; Goals; Growth; Health; Human; Human Development; Image; Image Analysis; Immune; Impairment; In Vitro; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Intestinal Diseases; Intestines; Investigation; Irritable Bowel Syndrome; Life; Life Experience; Life Stress; Link; Longevity; Modeling; Mucous Membrane; Mus; Muscarinic Acetylcholine Receptor; Muscarinic M3 Receptor; Nerve; Nervous system structure; Neurobiology; Outcome; Pathway interactions; Physiological; Predisposition; Prevention; Process; Production; Proteins; Research; Severities; Signal Pathway; Signal Transduction; Stress; Symptoms; System; TNF gene; Testing; Tight Junctions; Time Study; Tryptase; Weaning; Work; base; cholinergic; cholinergic neuron; design; feeding; gastrointestinal; gastrointestinal system; in vivo; in vivo Model; innovation; mast cell; new therapeutic target; novel; novel strategies; postnatal; prenatal; programs; protein structure function; public health relevance; response; stressor

DESCRIPTION (provided by applicant): The overall goal of this research is to understand the mechanisms by which early life stress triggers long-lasting defects in intestinal epithelial barrie function. The proposed studies with investigate the interactive signaling between the enteric cholinergic nervous system, intestinal mast cells, and the intestinal epithelial barrier utilizing novel pig and murine model systems. The project, based on previous studies and recent preliminary data, will test the hypothesis, that early life stress-associated GI disease is caused by a multistep mechanism in which long-term sensitization and increased abundance of cholinergic enteric nerves triggers persistent mast cell activation and subsequent intestinal barrier dysfunction. Understanding the early life signaling pathways that trigger long-lasting intestinal barrier dysfunction has relevance understanding the development of important human disorders including the Inflammatory Bowel Diseases (IBDs) and Irritable Bowel Syndrome (IBS). At the same time, these studies will have significant relevance to understanding and treating intestinal disease of agricultural animals such as the pig which undergo early life production stressors that have long-lasting deleterious influence on disease resistance, growth rate, and feed efficiency throughout the animal's production lifespan. In Specific Aim 1, we will determine the mechanism by which early life stress triggers long-term amplification of enteric cholinergic nervous system activity. In Specific Aim 2, we will utilize innovative in vitro and in vivo model systems to unravel the mechanisms by which Ach triggers persistent intestinal mast cell activation. In Specific Aim 3, we seek to understand the impact of early life stress and cholinergic nerve-mast cell signaling on alterations in epithelial tight junction protein function and structure in porcine and human models. These specific aims are designed to gain a fundamental understanding of how early life experiences contribute to the development of GI disease in adult life and will bring to light opportunities to develop novel approaches for the prevention and treatment of important GI diseases in humans and agricultural animals.

描述（由申请人提供）：本研究的总体目标是了解早期生活应激触发肠上皮巴里功能长期缺陷的机制。拟议的研究利用新型猪和小鼠模型系统研究肠胆碱能神经系统、肠肥大细胞和肠上皮屏障之间的相互作用信号。该项目基于以前的研究和最近的初步数据，将测试这一假设，即早期生活压力相关的胃肠道疾病是由多步骤机制引起的，其中长期致敏和胆碱能肠神经丰度增加引发持续的肥大细胞激活和随后的肠屏障功能障碍。了解触发长期肠屏障功能障碍的早期生命信号通路与了解重要人类疾病的发展相关，包括炎症性肠病（IBD）和肠易激综合征（IBS）。同时，这些研究将与理解和治疗农业动物（例如猪）的肠道疾病具有显著相关性，所述农业动物经历早期生活生产应激源，所述应激源在动物的整个生产寿命期间对抗病性、生长速率和饲料效率具有长期有害影响。在具体目标1中，我们将确定早期生活应激触发肠胆碱能神经系统活动长期放大的机制。在具体目标2中，我们将利用创新的体外和体内模型系统来解开乙酰胆碱触发持续性肠肥大细胞激活的机制。在具体目标3中，我们试图了解早期生活应激和胆碱能神经肥大细胞信号传导对猪和人类模型中上皮紧密连接蛋白功能和结构改变的影响。这些具体目标旨在从根本上了解早期生活经历如何促进成年后胃肠道疾病的发展，并将为开发预防和治疗人类和农业动物重要胃肠道疾病的新方法带来机会。