A role for the stomach in protection from colitis

胃在预防结肠炎中的作用

基本信息

批准号：
10339428
负责人：
DAVID L. BOONE
金额：
$ 50.66万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10339428
关键词：
Acute Affect American Amyloid Amyloid fibers Biological Response Modifier Therapy Chronic Colitis Cytoplasmic Granules Data Disease remission Environmental Risk Factor Epithelial Epithelial Cells Fiber Foundations Genetic Inflammation Inflammatory Bowel Diseases Interleukin-10 Intestinal Mucosa Intestines Knowledge Location Mediating Microbe Microbial Biofilms Modeling Molecular Mechanisms of Action Mucous Membrane Mucous body substance Mus Pathologic Processes Peptide Hydrolases Pharmacotherapy Population Predisposition Process Proteins Pulmonary Surfactant-Associated Protein C Pulmonary Surfactant-Associated Proteins Rag1 Mouse Resistance Role Signal Transduction Stomach T-Lymphocyte Testing Therapeutic Therapeutic Uses Trinitrobenzenesulfonic Acid Work amyloid formation amyloidogenesis base dextran sulfate sodium induced colitis dietary economic cost feeding gut inflammation gut microbes immune function microbial murine colitis novel strategies novel therapeutics protective effect societal costs

项目摘要

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.

项目摘要我们发现了在保护结肠炎的胃中的新功能。具体而言，我们发现一种称为胃刺1（GKN1）的蛋白质，仅制造胃中充足的肠子是必不可少的疾病（IBD）。以我们先前的发现为基础，即保护GKN1是必需的 DSS引起的结肠炎，我们发现GKN1是针对T细胞的保护所必需的介导的结肠炎。具体而言，gkn1 - / - 小鼠在TNBS中会出现更严重的结肠炎（三硝基苯磺酸）IBD的急性T细胞介导的模型。另外，我们的初步数据表明gkn1 - / - x rag1 - / - 小鼠在t中发展更严重的结肠炎 IBD模型的细胞转移模型。因此，GKN1（一种特异性蛋白质）可以保护反对结肠炎。 GKN1是一种小的稳定蛋白质，包含一个分泌信号和brichos 软骨瘤蛋白和肺表面活性剂蛋白c）结构域。分泌信号导致将gkn1包装到胃毛状上皮细胞的粘液颗粒中，并释放 GKN1进入胃腔。 Brichos域以有限的数量找到到目前为止，包括GKN1在内的所有哺乳动物蛋白质均为抗淀粉样蛋白生成。所有门类的微生物使分泌的淀粉样蛋白含有蛋白质促进生物膜形成。鉴于GKN1是具有抗淀粉样蛋白的腔蛋白活性我们测试了GKN1是否抑制微生物淀粉样蛋白的形成。我们的初步数据表明GKN1抑制微生物淀粉样纤维的形成和生物膜形成。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并保护结肠炎。我们将以以下目的检验该假设：（1）确定GKN1在保护免受慢性T细胞介导的结肠炎中的需求；（2）表征GKN1作用的分子机制；（3）确定功能 GKN1活性在保护侵害结肠炎中的作用。这些研究将非常重要，因为它们将定义GKN1的新要求，一种在胃中生产的蛋白质，可保护结肠炎。进一步这些研究将表征GKN1的分子机理，并暗示对肠道淀粉样蛋白免受结肠炎的保护。最后，我们检查预防措施的工作 GKN1的治疗喂养用于保护结肠炎可能打开新的治疗治疗IBD的机会。