Targeting ER Stress in Inflammatory Bowel Disease

 描述(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)中重要的遗传基因座突变与炎症性肠病(如克罗恩病和溃疡性结肠炎)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激活联系在一起。另一个与IBD相关并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，到目前为止，在IBD中是否存在UPR和NOD1/2先天免疫信号之间的联系还没有被探索。这项应用的目的是研究在炎症性肠病背景下，在UPR中NOD激活的作用。我们的中心假设是IBD期间肠上皮细胞中的内质网应激诱导依赖于NOD1/2信号的促炎反应。我们进一步提出，抑制内质网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提出的，该数据表明，与野生型对照相比，刺激Nod1/2/-缺陷的骨髓巨噬细胞或注射内质网应激诱导剂thapsigargin导致Nod1/2-/-小鼠的IL-6产生显著减少。我们计划通过追求以下具体目标来检验这一假设。目的1：探讨NOD1/2信号通路在内质网应激诱导的肠炎症中的作用。目的2：确定内质网应激的药物干预是否减轻IBD模型的炎症反应。这项拟议工作的成功完成对人类健康具有重要意义，因为它将阐明炎症性肠病中内质网应激与随后通过NOD1/2传感器的未折叠蛋白反应和先天免疫信号之间的联系。这项研究的基本原理是，阐明内质网应激和NOD信号在IBD过程中的相互作用将有助于开发新的创新的治疗方法，这将在这一应用中进行研究。这项拟议工作的成功完成将具有重要意义，因为它将帮助我们了解IBD的发病机制，这可能会导致新的干预策略的开发。

 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.