Mechanisms of Gastrointestinal Post-Inflammatory Disease

胃肠道炎症后疾病的机制

• 批准号: 10190923
• 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/10190923
• 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.

摘要： 腹泻型肠易激综合征(IBS-D)是最常见的 胃肠道疾病表现为腹痛、水样大便疏松和 在没有可识别的炎症、结构或代谢异常的情况下的紧迫感。一 最常见和最难治疗的IBS-D组是那些感染肠道疾病的人 由食物中毒引起的感染，随后发展为感染后腹泻为主， 肠易激综合征(PI-IBS-D)。迁延性腹泻与脏腑病机 结肠炎缓解后的伤害性感觉尚不清楚，还需要进一步的工作来 了解它的病理生理学。它给卫生保健资源带来了巨大的财政负担 并降低生活质量。不幸的是，对于PI-IBS-D的药物治疗仍然存在 有限且不能令人满意。因此，我们正在专注于这一亚群的患者进行研究 结肠炎后胃肠功能障碍的潜在机制。 我们现在有初步数据，为阵营发挥作用提供了非常强有力的理由- 反应元件转录因子(CREB)和miRNAs，导致阿片类基因减少 PI-IBS-D患者的表达。肠道感染改变胃肠功能和内脏 伤害性感觉导致PI-IBS-D。我们已经在PI-IBS-D患者中发现了miRNAs 受CREB信号通路调控，靶向结肠下游阿片基因 肠道神经系统与控制炎症后胃肠功能调节 和内脏伤害感。我们假设miRNAs失调了下游靶标。 在肠道感染后，通过改变CREB信号通路。这些新发现 提示PI-IBS-D涉及miRNAs等复杂调控通路的失调 通过下游目标进行互动。我们的实验室已经建立了创新的技术来 确定miRNAs在表观遗传表达调控中的细胞内和细胞内作用 它们下游的目标基因。这些方法包括miRNAs的相互作用分析；在 MiRNAs体外转染和体内注射miRNAs寡核苷酸。这些发现 将(I)阐明PI-IBS-D胃肠功能失调的机制 病人；(2)克服在以下病人管理方面取得进展的关键障碍 肠道感染和结肠炎--缺乏有效的治疗干预措施；(3)导致预防性 和/或对PI-IBS-D患者的治疗策略模仿或抑制特定的 MiRNAs对靶基因表达的影响。