Mechanisms of Altered Gastrointestinal Dysfunction

胃肠功能障碍的改变机制

基本信息

批准号：
9900345
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
项目类别：
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/9900345
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 Epithelium 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

项目摘要

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.

抽象的：以腹泻为主的肠易激综合征 (IBS-D) 是最常见的疾病之一胃肠道疾病，其特征是腹痛、稀稀水样便和在没有可识别的炎症、结构或代谢异常的情况下的紧急情况。最常见和最难治疗的 IBS-D 群体是那些患有肠道疾病的人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）持续性腹泻和内脏损伤的机制。结肠炎消退后的伤害感受尚不清楚，需要进一步的工作了解其病理生理学，这给医疗保健资源带来了巨大的经济负担。不幸的是，针对 PI-IBS-D 的药物治疗仍然存在。因此，我们将重点放在这一患者亚群上进行研究。结肠炎后胃肠功能障碍的根本机制。我们现在有了初步数据，为儿茶酚-O-的作用提供了非常有力的理由。甲基转移酶 (COMT) 和 miRNA 导致 PI-IBS-D 患者胃肠道功能障碍。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 患者中鉴定出受 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胃肠道功能和内脏伤害感受的调节。通过 COMT 信号传导肠道感染后下游靶点失调这些新发现表明 PI-IBS-D 涉及复合体的失调。我们的实验室拥有 miRNA 通过下游靶点相互作用的调控途径。确定 miRNA 在表观遗传中细胞间和细胞内作用的技术其下游靶基因表达的调控。 miRNA 的相互作用分析；miRNA 的体外转染和 miRNA 的体内注射；这些发现可能揭示寡核苷酸失调的机制。 PI-IBS-D 患者的胃肠功能这将克服进展的关键障碍。肠道感染和结肠炎患者的管理——缺乏有效的治疗干预措施并可能导致 PI-IBS-D 患者的预防和/或治疗策略模拟或抑制特定 miRNA 对靶基因表达的影响。