Mechanisms of Altered Gastrointestinal Dysfunction

胃肠功能障碍的改变机制

• 批准号: 10226821
• 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: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226821
• 关键词: Abdominal Pain; Address; Animal Model; Biological; Biological Factors; Catechol O-Methyltransferase; Cell Culture Techniques; Cell model; Cells; Chronic; Chronic diarrhea; Citrobacter rodentium; Clinical; Coculture Techniques; Colitis; Colon; Communication; Complex; Contracts; Data; Development; Diarrhea; Disease; Down-Regulation; Enteric Nervous System; Environment; Epithelial; Epithelial Cells; Feces; Financial Hardship; Food; Food Poisoning; Functional disorder; Gastrointestinal Diseases; Gene Expression; Genes; Grant; Healthcare; Human; In Vitro; Incubated; Individual; Infection; Inflammatory; Injections; Intervention; Intestines; Irritable Bowel Syndrome; Lead; Light; Link; Metabolic; Methods; MicroRNAs; Mus; Neurons; Neurotransmitters; Nociception; Oligonucleotides; Patients; Pharmaceutical Preparations; Pharmacology; Physiological; Preventive; Quality of life; Regulation; Regulatory Pathway; Resolution; Resources; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Structure; Symptoms; TNF gene; Techniques; Testing; Therapeutic; Tissue Model; Tissues; Transfection; Up-Regulation; Visceral; Visceral pain; Work; base; chronic abdominal pain; diagnostic biomarker; differential expression; effective therapy; endophenotype; enteric infection; epigenetic regulation; exosome; extracellular vesicles; gastrointestinal; gastrointestinal function; gastrointestinal symptom; genetic manipulation; high risk; in vivo; infliximab; innovation; intestinal epithelium; laser capture microdissection; mouse model; novel diagnostics; novel therapeutic intervention; patient subsets; single cell analysis; small molecule

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 mechanism(s) 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 underling mechanism(s) of post-colitis gastrointestinal dysfunction. We now have preliminary data that provides a very strong rationale for the role of Catechol-O- Methyl-Transferase (COMT) and miRNAs leading to GI dysfunction 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, modulated by COMT signaling pathways, that target downstream genes in the colonic enteric nervous system which control post-inflammatory regulation of gastrointestinal function and visceral nociception. We hypothesize that miRNAs dysregulate downstream targets following an enteric infection through altered COMT 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 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 may shed light on the mechanisms of dysregulation of gastrointestinal function in PI-IBS-D patients. This will overcome a critical barrier to progress in the management of patients following enteric infection and colitis–absence of effective treatment interventions and may 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： 腹泻为主的肠易激综合征（IBS-D）是最常见的 胃肠道疾病，表现为腹痛、稀水样便， 在没有可识别的炎症，结构或代谢异常的情况下的紧迫性。一 最常见和最难治疗的IBS-D组是那些患有肠易激综合征的人， 食物中毒感染，随后发展为感染后，以绦虫为主， 肠易激综合征（PI-IBS-D）。持续性腹泻和内脏损害的机制 结肠炎消退后的伤害感受尚不清楚，需要进一步的研究， 了解其病理生理学。这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，PI-IBS-D的药物治疗仍然存在， 有限且不令人满意。因此，我们正在集中对这一亚群患者进行研究 结肠炎后胃肠功能障碍的潜在机制。 我们现在有了初步的数据，为邻苯二酚-O-的作用提供了非常有力的依据。 甲基转移酶（COMT）和miRNA导致PI-IBS-D患者的GI功能障碍。 肠道感染改变胃肠道功能和内脏伤害感受，导致PI-IBS-D。 我们已经在PI-IBS-D患者中鉴定了由COMT信号通路调节的miRNA， 靶向结肠肠神经系统中控制炎症后的下游基因 调节胃肠功能和内脏伤害感受。我们假设miRNA 肠道感染后通过改变COMT信号传导失调下游靶点 途径。这些新的发现表明PI-IBS-D涉及复杂的 miRNA通过下游靶点相互作用的调节途径。我们的实验室 已建立的技术来确定miRNA在表观遗传中的细胞间和细胞内作用， 调控其下游靶基因的表达。这些方法包括 miRNA的相互作用分析; miRNA的体外转染;以及miRNA的体内注射 寡核苷酸这些发现可能揭示了调节失调的机制， PI-IBS-D患者的胃肠功能。这将克服在以下方面取得进展的关键障碍： 肠道感染和结肠炎患者的管理-缺乏有效的治疗 可能导致PI-IBS-D患者的预防和/或治疗策略， 模拟或抑制特定miRNA对靶基因表达的作用。