Claudin expression regulates mucus function

PAR-21-155 Capaldo 项目摘要： 炎症性肠病（IBD），包括克罗恩病（CD）和克罗恩病（MD）。 溃疡性结肠炎（UC）涉及反复的免疫激活和进行性降解 肠壁的损伤IBD是特发性疾病，目前的治疗方法经常不能 改善炎症症状，促进疾病进展。不良结局 可能是由于IBD发病机制的复杂性，其涉及遗传和 环境因素，如高脂肪，低纤维的西方饮食。因此，至关重要的是， 新的治疗策略在遗传易感性的背景下显示出疗效， IBD。该提案旨在探索基因相关IBD的新假说， 发病机制，并评估潜在的饮食疗法在基因敲除中的疗效 IBD小鼠模型。重要的是，肠道的细胞和/或粘液屏障的丧失， 所有人类IBD的共同病因学特征;包括粘液稠度的变化 和claudin蛋白表达。我们的初步数据表明， 基于密蛋白的屏障和粘液屏障之间的关系。因此本 一项提案将解决以下假设：炎症细胞因子破坏离子/液体 通过异常的claudin表达在结肠中的稳态，导致 削弱粘液屏障，增加疾病易感性。目标1将直接 测试炎症期间，claudin蛋白的功能是减少粘液 密度和粘液形成有效屏障的能力。虽然我们的初步数据 尽管这强烈支持这一假设，但目前还不清楚是否可以直接改变claudin 表情事实上，紧密连接蛋白的功能和调节知之甚少。然而，在这方面， 高纤维/可发酵纤维饮食已经在小鼠中被证明支持嗜粘液性 细菌在结肠，从而增加粘液密度和保护功能。威尔减肥法 支持粘液屏障的药物证明对患有遗传缺陷的患者有效， 削弱细胞屏障在目标2中，我们将确定粘液密度的增加是否 在IBD小鼠模型中具有治疗益处，肝细胞核因子α (HNF4敲除小鼠。HNF 4突变在UC和CD中发现，已被证明 导致claudin基因表达的变化，而肠道中Hnf 4a的去除是 足以引起小鼠结肠炎。我们将评估这些小鼠体内的粘液功能， 确定膳食纤维是否会减轻或加重小鼠的结肠炎症状， 遗传上易患慢性结肠炎

PAR-21-155 Capaldo Project Summary: Inflammatory Bowel Diseases (IBDs), encompassing both Crohn’s Disease (CD) and Ulcerative Colitis (UC), involve recurring immune activation and progressive degradation of the intestinal lining. IBDs are idiopathic diseases and current therapies frequently fail to ameliorate inflammatory symptoms, contributing to disease progression. Poor outcomes may be due to the complexities of IBD pathogenesis, which involve both genetic and environmental factors such as a high fat, low fiber western diet. Therefore, it is vital that new therapeutic strategies demonstrate efficacy in the context of genetic predisposition to IBD. This proposal aims to explore both a novel hypothesis for gene-related IBD pathogenesis, and evaluate the efficacy of a potential dietary therapy in a knockout mouse model of IBD. Importantly, loss of the cellular and/or mucus barriers of the gut is a common etiological feature of all human IBDs; including changes in mucus consistency and claudin protein expression. Our preliminary data suggest a novel functional relationship between the claudin-based barrier and the mucus barrier. Therefore, this proposal will address the following hypothesis: Inflammatory cytokines disrupt ion/fluid homeostasis in the colon through aberrant claudin expression, resulting in a weakened mucus barrier and increased susceptibility to disease. Aim 1 will directly test the hypothesis that, during inflammation, claudin proteins function to reduce mucus density and the ability of mucus to form an effective barrier. While our preliminary data strongly support this hypothesis, it is unclear if therapies can be directed at altering claudin expression. Indeed, claudin function and regulation is very poorly understood. However, high fiber/fermentable fiber diets have been demonstrated in mice to support mucophilic bacteria in the colon, thereby increasing mucus density and protective function. Will diets that support the mucus barrier prove effective in patients bearing genetic deficiencies that weaken the cellular barrier? In Aim 2 we will determine if an increase in mucus density has therapeutic benefit in a mouse model of IBD, Hepatocyte Nuclear Factor alpha (HNF4) knockout mice. HNF4 mutations are found in UC and CD, have been shown to cause changes in claudin gene expression, and removal of Hnf4a in the intestine is sufficient to cause colitis in mice. We will assess mucus function in these mice in vivo, and determine if dietary fiber will alleviate or exacerbate colitis symptoms in mice that are genetically predisposed to chronic colitis development.