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.

项目概要我们发现胃有预防结肠炎的新功能。具体来说，我们发现一种称为胃因子-1 (Gkn1) 的蛋白质，专门由胃中含量丰富，是预防肠道炎症所必需的疾病（炎症性肠病）。基于我们之前的发现，Gkn1 是保护免受 DSS 诱发的结肠炎，我们发现 Gkn1 是保护 T 细胞所必需的介导的结肠炎。具体来说，Gkn1-/- 小鼠在 TNBS 中出现更严重的结肠炎（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 区出现更严重的结肠炎 IBD模型的细胞转移模型。因此，Gkn1（一种胃特异性蛋白质）可以保护对抗结肠炎。 Gkn1 是一种小的稳定蛋白，含有分泌信号和 BRICHOS（Bri2、软骨调节蛋白和肺表面活性蛋白 C) 结构域。分泌信号导致将 Gkn1 包装到胃小凹上皮细胞的粘液颗粒中并释放 Gkn1 进入胃腔。 BRICHOS 域存在于有限数量的迄今为止研究的所有哺乳动物蛋白，包括 Gkn1，都具有抗淀粉样蛋白生成。所有门的微生物都会分泌含有淀粉样蛋白的蛋白质促进生物膜形成。鉴于 Gkn1 是一种具有抗淀粉样蛋白生成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形成的活性。我们的初步数据表明 Gkn1 抑制微生物淀粉样纤维形成和生物膜形成。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 细胞介导的结肠炎方面的需求； (2) 表征Gkn1作用的分子机制； (3) 确定泛函 Gkn1 活性在预防结肠炎中的作用。这些研究一起将具有重要意义，因为它们将为 Gkn1 定义新的要求，胃中产生的蛋白质，可预防结肠炎。进一步这些研究将表征 Gkn1 的分子作用机制并暗示其控制肠道淀粉样蛋白可预防结肠炎。最后，我们的工作审查预防性 Gkn1 保护结肠炎的治疗性喂养可能开辟新的治疗方法 IBD 治疗的机会。