A role for the stomach in protection from colitis

项目摘要 我们发现了胃预防结肠炎的一种新功能。 具体地说，我们发现一种名为胃动素-1(GKN1)的蛋白质，专门制造 并在胃中大量存在，是预防肠道发炎所必需的 疾病(IBD)。基于我们之前的发现，需要GKN1来保护 DSS诱导的结肠炎，我们发现GKN1是T细胞保护所必需的 介质性结肠炎。具体地说，GKN1-/-小鼠在TNBS中发展为更严重的结肠炎 (三硝基苯磺酸)急性T细胞介导的IBD模型。此外，我们的 初步数据表明，GKN1-/-x RAG1-/-小鼠在T期发展为更严重的结肠炎 炎性肠病模型的细胞转移模型。因此，胃特异性蛋白质GKN1可以保护 治疗结肠炎。 GKN1是一种稳定的小蛋白，含有分泌信号和Brichos(Bri2， 软骨调节素和肺表面活性物质蛋白C)结构域。分泌信号导致 胃小凹上皮细胞黏液颗粒包装GKN-1及其释放 GKN1进入胃腔。Brichos域存在于有限数量的 到目前为止研究过的所有哺乳动物蛋白质，包括GKN1，都是抗 淀粉样变性。所有门的微生物都会分泌含有淀粉样蛋白的蛋白质来 促进生物膜的形成。鉴于GKN1是一种具有抗淀粉样变性作用的管腔蛋白 我们测试了GKN1是否抑制微生物淀粉样蛋白的形成。我们的预赛 数据表明，GKN1抑制微生物淀粉样纤维的形成和生物膜的形成。 我们假设GKN1的Brichos结构域抑制基于淀粉样蛋白的微生物 生物膜和预防结肠炎。我们将通过以下目标来检验这一假设：(1) 确定GKN1在预防慢性T细胞介导的结肠炎中的需求；(2) 研究GKN1的分子作用机制；(3)测定GKN1的功能 GKN1活性在预防结肠炎中的作用。 这些研究加在一起将具有重要意义，因为它们将为GKN1定义一个新的要求， 一种在胃中制造的蛋白质，用于预防结肠炎。进一步的这些研究将 阐明GKN1的分子作用机制及其调控作用 肠道淀粉样蛋白对结肠炎的保护作用。最后，我们的工作审查预防性 而GKN1的治疗性喂养保护结肠炎可能开辟新的治疗方法 治疗IBD的机会。

Project Summary We have discovered a new function for the stomach in protection from colitis. Specifically, we have found that a protein called gastrokine-1 (Gkn1), made exclusively and abundantly in the stomach, is required for protection against inflammatory bowel disease (IBD). Building on our previous finding that Gkn1 is required for protection from DSS-induced colitis, we have found that Gkn1 is required for protection against T cell mediated colitis. Specifically, Gkn1-/- mice develop more severe colitis in the TNBS (trinitrobenzenesulfonic acid) acute T cell mediated model of IBD. In addition, our preliminary data suggest that Gkn1-/- x RAG1-/- mice develop more severe colitis in the T cell transfer model of model of IBD. Thus Gkn1, a stomach specific protein, protects against colitis. Gkn1 is a small stable protein containing a secretion signal and a BRICHOS (Bri2, chondromodulin, and lung surfactant protein C) domain. The secretion signal results in packaging of Gkn1 into mucus granules of gastric foveolar epithelial cells and release of Gkn1 into the gastric lumen. The BRICHOS domain is found in a limited number of mammalian proteins, all of which studied thus far, including Gkn1, are anti- amyloidogenic. Microbes across all phyla make secreted amyloid containing proteins to facilitate biofilm formation. Given that Gkn1 is a lumenal protein with anti-amyloidogenic activity we tested whether Gkn1 inhibits microbial amyloid formation. Our preliminary data indicates that Gkn1 inhibits microbial amyloid fiber formation and biofilm formation. We hypothesize that the BRICHOS domain of Gkn1 inhibits amyloid based microbial biofilms and protects from colitis. We will test this hypothesis with the following aims: (1) Determine the requirement for Gkn1 in protection from chronic T cell mediated colitis; (2) Characterize the molecular mechanism of action of Gkn1; (3) Determine the functional role of Gkn1 activity in protection from colitis. Together these studies will be significant as they will define a new requirement for Gkn1, a protein made in the stomach, in protection from colitis. Further these studies will characterize the molecular mechanism of action of Gkn1 and implicate control of intestinal amyloids in protection from colitis. Lastly, our work examining preventative and therapeutic feeding of Gkn1 for protection of colitis may open new therapeutic opportunities for treatment of IBD.