Mechanisms of Gastrointestinal Post-Inflammatory Disease

胃肠道炎症后疾病的机制

基本信息

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
项目类别：
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

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 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和特征是腹痛，粪便松散和在没有可识别的炎症，结构或代谢异常的情况下，紧迫性。一在最常见和难以治疗的IBS-D组中，那些签约的人食物中毒感染，随后发展出感染后的，腹泻促进性，肠易激综合征（PI-IBS-D）。持续性腹泻和内脏的机制结肠炎解决后的伤害感受尚不清楚，需要进一步的工作才能了解其病理生理学。它对医疗保健资源造成了巨大的财务燃烧并发展生活质量。不幸的是，PI-IBS-D的药物疗法仍然存在有限且不令人满意。因此，我们专注于研究患者的亚群胃炎后胃炎功能障碍的基本机制。现在，我们拥有初步数据，为训练营的角色提供了非常有力的理由。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。肠感染改变胃肠道功能和内脏伤害感受导致pi-ibs-d。我们已经确定了PI-IBS-D患者中的miRNA 由CREB信号通路调节，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炎症后调节和内脏的nocect。我们假设miRNA失调下游靶标通过改变CREB信号通路后肠道感染。这些新发现表明PI-IBS-D涉及复杂调节途径的失调，其中miRNA 通过下游目标进行交互。我们的实验室已经建立了创新技术确定miRNA在表达的表观遗传调节中的细胞间和细胞内作用其下游靶基因。这些方法包括对miRNA的相互作用分析；在 miRNA的体外转染；并在体内注射miRNA寡核苷酸。这些发现（i）阐明PI-IBS-D中胃肠功能失调的机制患者; （ii）克服在患者管理中进展的关键障碍肠道感染和结肠炎 - 有效治疗干预措施；（iii）导致预防和/或理论策略在模仿或抑制特定影响的PI-IBS-D患者中靶基因表达上的miRNA。