Somatic Hypersensitivity in Veterans with IBS

患有肠易激综合症的退伍军人的躯体过敏

• 批准号: 8496479
• 负责人: George Nicholas Verne
• 金额: --
• 依托单位: CINCINNATI VA MEDICAL CENTER RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8496479
• 关键词: Abdominal Pain; Allergic inflammation; Bacteria; Cell Culture System; Cell Culture Techniques; Cell Membrane Permeability; Cells; Chronic; Constipation; Data; Defect; Diarrhea; Disease; Functional disorder; Funding; Genes; Glutamate-Ammonia Ligase; Glutamine; Goals; Human; Hypersensitivity; In Vitro; Inflammation; Intestines; Irritable Bowel Syndrome; Lead; Mediating; MicroRNAs; Modeling; Pathway interactions; Patients; Permeability; Research; Signal Pathway; Site; Stress; Symptoms; Therapeutic Agents; Toxin; Untranslated Regions; Veterans; inhibitor/antagonist; novel; novel therapeutic intervention; tissue culture; tissue/cell culture

DESCRIPTION (provided by applicant): Our VA-funded research team has identified deployed veterans with chronic GI symptoms who have increased intestinal permeability. Although the pathophysiology of chronic GI symptoms is unknown, increased intestinal permeability could be a major contributing factor. The increased intestinal permeability itself may be due to several factors including stress, inflammation, allergc disorders and/or through decreased glutamine synthetase activity, resulting in decreased intestinal glutamine levels. Our recent study demonstrated that increased expression of miR-29a leads to decreased glutamine synthetase levels and increased intestinal permeability through glutamine dependent mechanisms (Zhou et al., 2010). These data strongly suggest that glutamine may serve as a potential therapeutic agent for veterans with IBS and increased intestinal permeability and the signaling pathway of miRNA-modulated targets could lead to new therapeutic approaches. We now have preliminary data for veterans with chronic GI symptoms and increased intestinal permeability indicating increased colonic expression of miR-124 and miR-373. The mechanisms by which miR-124 and miR-373 modulates intestinal permeability may be through glutamine synthetase pathways. Interestingly, miR- 124 and miR-373 expression is increased in deployed veterans with GI symptoms but not in asymptomatic deployed veterans. Thus, our studies will provide a novel model that explains the mechanism underlying increased permeability and GI symptoms in deployed veterans and suggest new ways to treat these veterans. The first aim of our study is to determine if the mechanisms of interaction between (a) miR-124 and miR- 373 expression and (b) if chronic GI symptoms/increased intestinal permeability in veterans occurs through glutamine-dependent or glutamine-independent signaling pathways. Our second aim is to characterize key pathways involved in miR-124 and miR-373 mediated mucosal barrier defects by using cell culture techniques. This aim will be accomplished using in vitro cell and/or tissue culture to determine if (1) miR-124 and miR-373 over expression directly inhibits glutamine synthetase expression, which leads to increased intestinal permeability; and/or (2) if miR-124 and miR-373 expression directly alters intestinal permeability through a glutamine independent signaling pathway.

描述（由申请人提供）： 我们的VA资助研究团队已经确定了具有慢性胃肠道症状的退伍军人，这些退伍军人的肠道通透性增加了。尽管慢性胃肠道症状的病理生理尚不清楚，但肠道通透性增加可能是主要因素。肠道渗透率增加可能是由于多种因素引起的，包括压力，炎症，过敏性疾病和/或谷氨酰胺合成酶活性降低，导致肠谷氨酰胺水平降低。我们最近的研究表明，miR-29a的表达增加会导致谷氨酰胺合成酶水平降低，并通过依赖谷氨酰胺的机制增加肠道通透性（Zhou等，2010）。这些数据强烈表明，谷氨酰胺可以作为具有IBS的退伍军人和增加肠道通透性的潜在治疗剂，而miRNA调节靶标的信号传导途径可能会导致新的治疗方法。 现在，我们拥有具有慢性胃肠道症状的退伍军人的初步数据，并增加了肠道通透性，表明miR-124和miR-373的结肠表达增加。 miR-124和miR-373调节肠道通透性的机制可能通过谷氨酰胺合成酶途径。有趣的是，在有胃肠道症状的部署退伍军人中，miR-124和miR-373表达增加，但在无症状的部署退伍军人中没有增加。因此，我们的研究将提供一个新型模型，该模型解释了部署的退伍军人的渗透率和胃肠道症状的增加的机制，并提出了治疗这些退伍军人的新方法。 我们研究的第一个目的是确定（a）miR-124和miR-373表达之间的相互作用机制以及（b）是否是否通过依赖谷氨酰胺依赖性或谷氨酰胺独立的信号通路发生慢性GI症状/退伍军人的肠道通透性增加。我们的第二个目的是通过使用细胞培养技术来表征miR-124和miR-373介导的粘膜屏障缺陷中涉及的关键途径。将使用体外细胞和/或组织培养来实现此目的 （1）miR-124和miR-373超过表达直接抑制谷氨酰胺合成酶表达，从而导致肠道通透性增加；和/或（2）如果miR-124和miR-373表达直接通过谷氨酰胺独立的信号通路改变肠道通透性。