Mechanisms of Gastrointestinal Post-Inflammatory Disease

胃肠道炎症后疾病的机制

• 批准号: 10166439
• 负责人: George Nicholas Verne
• 金额: $ 34.2万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10166439
• 关键词: Abdominal Pain; Address; Animal Model; Biological; Biological Factors; Cell Culture Techniques; Cells; Chronic; Chronic diarrhea; Colitis; Colon; Complex; Contracts; Cyclic AMP Response Element; Data; Development; Diarrhea; Disease; Enteral; Enteric Nervous System; Feces; Financial Hardship; Food; Food Poisoning; Functional disorder; Gastrointestinal Diseases; Gene Expression; Genes; Healthcare; Human; In Vitro; Infection; Inflammatory; Injections; Intervention; Intrathecal Injections; Irritable Bowel Syndrome; Knockout Mice; Laboratories; Lead; Light; Link; Mediating; Metabolic; Methods; MicroRNAs; Modeling; Molecular; Mus; Nervous System control; Neuronal Plasticity; Neurons; Neurotransmitters; Nociception; Oligonucleotides; Opioid; Opioid Receptor; Patients; Pharmaceutical Preparations; Pharmacology; Preventive; Quality of life; Regulation; Regulatory Pathway; Resolution; Resources; Role; Signal Pathway; Signal Transduction; Structure; System; Techniques; Therapeutic; Therapeutic Uses; Tissues; Transfection; Transgenic Mice; Up-Regulation; Visceral; Work; base; diagnostic biomarker; effective therapy; enteric infection; epigenetic regulation; experimental study; gastrointestinal; gastrointestinal function; gastrointestinal symptom; high risk; in vivo; inhibitor/antagonist; innovation; laser capture microdissection; novel; novel therapeutic intervention; novel therapeutics; patient subsets; small molecule; transcription factor

ABSTRACT: Diarrhea-predominant, irritable bowel syndrome (IBS-D) is one of the most frequent gastrointestinal disorders seen and is characterized by abdominal pain, loose watery stools, and urgency in the absence of an identifiable inflammatory, structural, or metabolic abnormality. One of the most common and difficult to treat IBS-D groups are those who contract an enteric infection from food poisoning and subsequently develop post-infectious, diarrhea-predominant, irritable bowel syndrome (PI-IBS-D). The mechanisms of persistent diarrhea and visceral nociception following resolution of the colitis are unclear and further work is needed to understand its pathophysiology. It puts an enormous financial burden on health care resources and decreases quality of life. Unfortunately, pharmacologic therapies for PI-IBS-D remain limited and unsatisfactory. Therefore, we are focusing on this subpopulation of patients to study the underlying mechanisms of post-colitis gastrointestinal dysfunction. We now have preliminary data that provide a very strong rationale for a role for the cAMP- response element transcription factor (CREB) and miRNAs, leading to decreased opioid gene expression in PI-IBS-D patients. Enteric infections alter gastrointestinal function and visceral nociception leading to PI-IBS-D. We have identified miRNAs in PI-IBS-D patients that are modulated by CREB signaling pathways, that target downstream opioid genes in the colonic enteric nervous system and that control post-inflammatory regulation of gastrointestinal function and visceral nociception. We hypothesize that miRNAs dysregulate downstream targets following an enteric infection through altered CREB signaling pathways. These new findings suggest that PI-IBS-D involves dysregulation of complex regulatory pathways in which miRNAs interact through downstream targets. Our lab has established innovative techniques to determine inter- and intra-cellular roles of miRNAs in the epigenetic regulation of the expression of their down-stream target genes. These methods include interaction analysis of miRNAs; in vitro transfection of miRNAs; and in vivo injection of miRNAs oligonucleotides. These findings will (i) shed light on the mechanisms of dysregulation of gastrointestinal function in PI-IBS-D patients; (ii) overcome a critical barrier to progress in the management of patients following enteric infection and colitis–absence of effective treatment interventions; (iii) lead to preventive and/or therapeutic strategies in PI-IBS-D patients that mimic or inhibit the effects of specific miRNAs on target gene expression.

抽象的： 腹泻促进，肠易激综合症（IBS-D）是最常见的 胃肠道疾病看到并以腹痛，宽松的粪便和 在没有可识别的炎症，结构或代谢异常的情况下进行紧迫 最常见和治疗IBS-D组的最常见的是肠 感染食物中毒，随后发展出感染后的腹泻促进性， 肠易激综合征（pi-ibs-d）。 结肠炎的Nocation储至分辨率尚不清楚，需要进一步的工作才能 理解是病理生理学。 不幸的是，降低生活质量。 因此，有限和不稳定。 胃炎后肠炎功能障碍的基本机制。 现在，我们有了初步数据，为营地的角色提供了一个非常适合的理由。 响应元素转录因子（CREB）和miRNA，导致阿片类药物基因降低 PI-IBS-D患者的表达。 导致Pi-ibs-d的Nocation。 由CREB信号通路模块化，该通路靶向下游阿片类药物基因 肠神经系统和胃肠道功能的控制后调节 和内脏的伤害感受。 通过改变CREB信号通路后的肠道感染 表明PI-IBS-D涉及复杂的规则性途径失调，其中miRNA 通过下游目标进行互动。 确定miRNA在表达的表观遗传调节中的细胞间和细胞内作用 它们的下游靶基因。 miRNA的体外转染； 遗嘱（i）阐明pi-ibs-d中胃静脉功能失调的机制 患者（ii）克服了患者管理的关键障碍 肠道感染和结肠炎 - 缺乏有效的治疗间隔； 和/或模仿或抑制特定作用的PI-IBS-D患者的治疗策略 靶基因表达上的miRNA。