Somatic Hypersensitivity in Veterans with IBS

描述(由申请人提供)： 我们由退伍军人管理局资助的研究团队已经确定了具有慢性胃肠道症状的部署退伍军人，他们的肠道通透性增加。虽然慢性胃肠道症状的病理生理学机制尚不清楚，但肠道通透性增加可能是一个主要因素。肠道通透性的增加本身可能是由于几个因素，包括应激、炎症、过敏性疾病和/或通过谷氨酰胺合成酶活性下降，导致肠道谷氨酰胺水平下降。我们最近的研究表明，miR-29a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机制增加肠道通透性(周等人，2010)。这些数据有力地表明，谷氨酰胺可能成为退伍军人IBS的潜在治疗药物，肠道通透性增加和miRNA调节靶点的信号通路可能导致新的治疗方法。我们现在有了有慢性胃肠道症状和肠道通透性增加的退伍军人的初步数据，表明结肠中miR-124和miR-373的表达增加。MiR-124和miR-373调节肠道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的表达在有胃肠道症状的退伍军人中增加，但在无症状的退伍军人中不增加。因此，我们的研究将提供一个新的模型，解释部署的退伍军人渗透性增加和胃肠道症状的潜在机制，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)退伍军人慢性胃肠道症状/肠道通透性增加是否通过谷氨酰胺依赖或谷氨酰胺非依赖的信号通路发生。我们的第二个目标是利用细胞培养技术研究miR-124和miR-373介导的粘膜屏障缺陷所涉及的关键途径。这一目标将通过使用体外细胞和/或组织培养来确定 (1)miR-124和miR-373的过度表达直接抑制谷氨酰胺合成酶的表达，从而导致肠道通透性增加；和/或(2)miR-124和miR-373的过度表达是否通过谷氨酰胺不依赖的信号通路直接改变肠道通透性。 公共卫生相关性： 慢性胃肠道症状在部署的退伍军人中很常见(腹痛、腹胀、腹泻、便秘)。有这些慢性胃肠道症状的退伍军人有肠道和身体的过敏反应，这可能归因于细菌和毒素可能穿透肠壁的“泄漏肠道”，称为肠道通透性增加。拟议研究的一个主要目标是确定导致肠道通透性增加的机制，这些机制可能随后导致部署的退伍军人出现慢性胃肠道症状，包括腹痛和腹泻。对这些机制的更好理解可能会导致治疗患有慢性胃肠道症状的退伍军人的新的潜在疗法。

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. PUBLIC HEALTH RELEVANCE: Chronic GI symptoms are common (abdominal pain, bloating, diarrhea, constipation) amoung deployed veterans. Veterans with these chronic GI symptoms have hypersenstivity of the gut and body which may be attributed to a "leaky gut" in which bacteria and toxins may penetrate the gut wall, termed increased intestinal permeability. A major goal of the proposed studies is to determine the mechanisms that lead to increased intestinal permeability that may subsequently lead to chronic GI symptoms, including abdominal pain and diarrhea, in deployed veterans. A better understanding of these mechanisms may lead to new potential therapies to treat veterans with chronic GI symptoms.