Somatic Hypersensitivity in Veterans with IBS

描述（由申请人提供）： 我们的VA资助的研究小组已经确定了部署退伍军人与慢性胃肠道症状谁增加了肠道通透性。虽然慢性胃肠道症状的病理生理学尚不清楚，但肠道通透性增加可能是一个主要因素。增加的肠渗透性本身可能是由于几种因素，包括应激、炎症、过敏性疾病和/或通过降低谷氨酰胺合成酶活性，导致肠谷氨酰胺水平降低。我们最近的研究表明，miR-29 a的表达增加导致谷氨酰胺合成酶水平降低，并通过谷氨酰胺依赖性机制增加肠通透性（Zhou et al.，2010年）。这些数据有力地表明，谷氨酰胺可能作为一种潜在的治疗剂，退伍军人与IBS和增加肠道通透性和miRNA调节的目标的信号通路可能会导致新的治疗方法。 我们现在已经有了退伍军人慢性胃肠道症状和肠通透性增加的初步数据，表明miR-124和miR-373的结肠表达增加。miR-124和miR-373调节肠通透性的机制可能是通过谷氨酰胺合成酶途径。有趣的是，miR- 124和miR-373的表达在有GI症状的退伍军人中增加，但在无症状的退伍军人中没有增加。因此，我们的研究将提供一种新的模型，解释部署退伍军人的渗透性增加和胃肠道症状的机制，并提出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）退伍军人中慢性GI症状/肠通透性增加是否通过谷氨酰胺依赖性或谷氨酰胺非依赖性信号传导途径发生。我们的第二个目标是通过使用细胞培养技术来表征参与miR-124和miR-373介导的粘膜屏障缺陷的关键途径。这一目的将通过体外细胞和/或组织培养来实现，以确定是否 (1)miR-124和miR-373过表达直接抑制谷氨酰胺合成酶表达，这导致肠通透性增加;和/或（2）如果miR-124和miR-373表达通过谷氨酰胺非依赖性信号传导途径直接改变肠通透性。

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.