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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：
10552043
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 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10552043
关键词：
Acute Affect American Amyloid Amyloid fibers Biological Response Modifier Therapy Chronic Colitis Cytoplasmic Granules Data Disease remission Environmental Risk Factor Epithelial Cells Epithelium 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 dextran sulfate sodium induced colitis dietary economic cost feeding gut inflammation gut microbes immune function microbial murine colitis novel strategies novel therapeutic intervention 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胃在保护结肠炎方面的新功能。具体来说，我们发现一种叫做gastrokine-1（Gkn 1）的蛋白质，在胃中大量存在，是保护肠道免受炎症所必需的。疾病（IBD）。基于我们之前的发现，Gkn 1是保护免受 DSS诱导的结肠炎，我们发现Gkn 1是保护T细胞所必需的。介导的结肠炎。具体地说，Gkn 1-/-小鼠在TNBS中发展出更严重的结肠炎。（三硝基苯磺酸）急性T细胞介导的IBD模型。另外我们初步数据表明，Gkn 1-/- x RAG 1-/-小鼠在T细胞中发生更严重的结肠炎， IBD模型的细胞转移模型。因此，Gkn 1，一种胃特异性蛋白，对抗结肠炎 Gkn 1是含有分泌信号和BRICHOS的小的稳定蛋白质（Bri 2，软骨调节素和肺表面活性蛋白C）结构域。分泌信号导致将Gkn 1包装到胃小凹上皮细胞的粘液颗粒中，并释放Gkn 1。 Gkn 1进入胃腔。BRICHOS域名存在于有限数量的哺乳动物的蛋白质，迄今为止研究的所有蛋白质，包括Gkn 1，都是抗淀粉样变所有门的微生物都分泌含有淀粉样蛋白的蛋白质，促进生物膜形成。鉴于Gkn 1是一种具有抗淀粉样蛋白生成作用的腔内蛋白活性，我们测试了Gkn 1是否抑制微生物淀粉样蛋白的形成。我们的初步数据表明Gkn 1抑制微生物淀粉样纤维形成和生物膜形成。我们假设Gkn 1的BRICHOS结构域抑制基于淀粉样蛋白的微生物生物膜和保护免受结肠炎。我们将以下列目标来检验这个假设：（1）确定Gkn 1在慢性T细胞介导的结肠炎保护中的需求;（2）研究Gkn 1的分子作用机制;（3）确定Gkn 1的功能 Gkn 1活性在结肠炎保护中的作用。这些研究将具有重要意义，因为它们将定义Gkn 1的新要求，一种在胃中产生的蛋白质，用于预防结肠炎。这些研究将表征Gkn 1的分子作用机制，并暗示肠淀粉样蛋白对结肠炎的保护作用。最后，我们的工作是检查预防措施治疗性喂养Gkn 1以保护结肠炎可能会开辟新的治疗方法治疗IBD的机会。