Targeting ER Stress in Inflammatory Bowel Disease

针对炎症性肠病的内质网应激

• 批准号: 9019324
• 负责人: Arina Marijke Keestra-Gounder
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9019324
• 关键词: Area; Automobile Driving; Autophagocytosis; Biological; Bone Marrow; Cell Line; Cell membrane; Cell physiology; Chronic; Colitis; Crohn' s disease; Data; Development; Disease; Environmental Risk Factor; Epithelial Cells; Future; Gastrointestinal tract structure; Genes; Genetic; Health; Human; Immune; Immune system; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Inherited; Injection of therapeutic agent; Interleukin-6; Intervention; Intestines; Knockout Mice; Knowledge; Lead; Link; Modeling; Mus; Mutation; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Play; Production; Proteins; Recruitment Activity; Regulation; Research; Research Project Grants; Role; Signal Pathway; Signal Transduction; Site; Symptoms; Testing; Thapsigargin; Ulcerative Colitis; United States; Viral; Virus; Work; base; endoplasmic reticulum stress; in vitro Model; in vivo; inhibitor/antagonist; innovation; loss of function; macrophage; mouse model; public health relevance; research study; response; sensor; tauroursodeoxycholic acid

 DESCRIPTION (provided by applicant) Mutations in genetic loci that are important in autophagy (ATG16L1), the unfolded protein response (XBP1) and in innate immune sensing (NOD2) have been associated with inflammatory bowel diseases like Crohn's disease and ulcerative colitis. The autophagy protein ATG16L1 is recruited to the cell membrane by NOD1 and NOD2 at the site of bacterial invasion, thereby linking autophagy and NOD activation. Another cellular process that is linked to IBD and is closely related to autophagy is the unfolded protein response (UPR), which is induced by endoplasmic reticulum (ER) stress. However, whether there is a connection between the UPR and NOD1/2 innate immune signaling in IBD has thus far not been explored. The objectives of this application are to study the role of NOD activation within the UPR in the context of inflammatory bowel disease. Our central hypothesis is that ER stress in intestinal epithelial cells during IBD induces a pro-inflammatory response that is dependent on NOD1/2 signaling. We further propose that drugs that inhibit ER stress can alleviate IBD symptoms. Our hypothesis has been formulated based on strong preliminary data demonstrating that stimulation of Nod1/2-/- deficient bone marrow derived macrophages or injection of Nod1/2-/- mice with the ER stress inducer thapsigargin resulted in a significant decrease in IL-6 production compared to wild type controls. We plan to test this hypothesis by pursuing the following specific aims. Aim 1: Determine the role of the NOD1/2 signaling pathway for ER stress induced inflammation in the intestine. Aim 2: Determine whether pharmacological intervention of ER stress alleviates inflammation in models of IBD. Successful completion of the proposed work is of relevance to human health because it will elucidate the connection of ER stress in intestinal epithelial cells and the subsequent unfolded protein response and innate immune signaling via the NOD1/2 sensors in inflammatory bowel disease. The rationale of the proposed research is that elucidating the interaction between ER stress and NOD signaling during IBD will aid in the development of new and innovative approaches for treatment, which will be studied in this application. Successful completion of the proposed work will be significant because it will help us gain knowledge on the pathogenesis of IBD that may lead to the development of new intervention strategies.

 描述（由申请人提供） 在自噬（ATG16L1）、未折叠蛋白反应（XBP1）和先天免疫感应（NOD2）中重要的基因位点突变与克罗恩病和溃疡性结肠炎等炎症性肠病有关。自噬蛋白 ATG16L1 在细菌入侵部位被 NOD1 和 NOD2 募集到细胞膜上，从而将自噬和 NOD 激活联系起来。另一个与 IBD 相关且与自噬密切相关的细胞过程是未折叠蛋白反应 (UPR)，它是由内质网 (ER) 应激诱导的。然而，迄今为止，IBD 中 UPR 和 NOD1/2 先天免疫信号之间是否存在联系尚未被探索。本申请的目的是研究 UPR 内 NOD 激活在炎症性肠病中的作用。我们的中心假设是 IBD 期间肠上皮细胞的 ER 应激会诱导依赖于 NOD1/2 信号传导的促炎症反应。我们进一步提出抑制 ER 应激的药物可以缓解 IBD 症状。我们的假设是基于强有力的初步数据制定的，这些数据表明，与野生型对照相比，刺激 Nod1/2-/- 缺陷骨髓来源的巨噬细胞或注射 ER 应激诱导剂毒胡萝卜素的 Nod1/2-/- 小鼠会导致 IL-6 产量显着减少。我们计划通过追求以下具体目标来检验这一假设。目标 1：确定 NOD1/2 信号通路在 ER 应激诱导的肠道炎症中的作用。目标 2：确定 ER 应激的药物干预是否可以减轻 IBD 模型中的炎症。成功完成拟议的工作与人类健康相关，因为它将阐明肠上皮细胞中的 ER 应激与随后的未折叠蛋白反应以及炎症性肠病中通过 NOD1/2 传感器的先天免疫信号传导之间的联系。拟议研究的基本原理是，阐明 IBD 期间 ER 应激与 NOD 信号传导之间的相互作用将有助于开发新的创新治疗方法，本申请将对此进行研究。成功完成拟议的工作将具有重要意义，因为它将帮助我们获得有关 IBD 发病机制的知识，从而可能导致制定新的干预策略。