Targeting ER Stress in Inflammatory Bowel Disease

针对炎症性肠病的内质网应激

基本信息

项目摘要

 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.
 在自噬(ATG 16 L1)、未折叠蛋白应答(XBP 1)和先天免疫感应(NOD 2)中重要的遗传基因座中的突变与炎性肠病如克罗恩病和溃疡性结肠炎相关。自噬蛋白ATG 16 L1被NOD 1和NOD 2在细菌入侵位点募集到细胞膜上,从而将自噬和NOD活化联系起来。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),其由内质网(ER)应激诱导。然而,迄今为止,IBD中UPR和NOD 1/2先天免疫信号传导之间是否存在联系尚未探索。本申请的目的是研究炎症性肠病背景下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ER应激诱导依赖于NOD 1/2信号的促炎反应。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,这些数据表明,与野生型对照相比,Nod 1/2-/-缺陷型骨髓来源的巨噬细胞的刺激或用ER应激诱导剂毒胡萝卜素注射Nod 1/2-/-小鼠导致IL-6产生的显著降低。我们计划通过追求以下具体目标来检验这一假设。目的1:确定NOD 1/2信号通路在内质网应激诱导的肠道炎症中的作用。目的2:确定ER应激的药物干预是否加重IBD模型的炎症。成功完成所提出的工作与人类健康有关,因为它将阐明肠上皮细胞中ER应激与随后的未折叠蛋白反应和炎症性肠病中通过NOD 1/2传感器的先天免疫信号传导的联系。拟议研究的基本原理是阐明IBD期间ER应激和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,这将在本申请中进行研究。成功完成拟议的工作将是重要的,因为它将帮助我们获得有关IBD发病机制的知识,这可能导致新的干预策略的发展。

项目成果

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Arina Marijke Keestra-Gounder其他文献

Arina Marijke Keestra-Gounder的其他文献

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{{ truncateString('Arina Marijke Keestra-Gounder', 18)}}的其他基金

The impact of ER stress on Salmonella Typhimurium infections
内质网应激对鼠伤寒沙门氏菌感染的影响
  • 批准号:
    10708073
  • 财政年份:
    2022
  • 资助金额:
    $ 23.33万
  • 项目类别:
The impact of ER stress on Salmonella Typhimurium infections
内质网应激对鼠伤寒沙门氏菌感染的影响
  • 批准号:
    10565316
  • 财政年份:
    2022
  • 资助金额:
    $ 23.33万
  • 项目类别:
NOD2 promotes coxsackievirus entry and pathogenesis
NOD2促进柯萨奇病毒进入和发病机制
  • 批准号:
    10407068
  • 财政年份:
    2021
  • 资助金额:
    $ 23.33万
  • 项目类别:
NOD2 promotes coxsackievirus entry and pathogenesis
NOD2促进柯萨奇病毒进入和发病机制
  • 批准号:
    10285845
  • 财政年份:
    2021
  • 资助金额:
    $ 23.33万
  • 项目类别:
Activation of the NOD1 and NOD2 signaling pathways
NOD1 和 NOD2 信号通路的激活
  • 批准号:
    10041261
  • 财政年份:
    2020
  • 资助金额:
    $ 23.33万
  • 项目类别:
Activation of the NOD1 and NOD2 signaling pathways
NOD1 和 NOD2 信号通路的激活
  • 批准号:
    10172844
  • 财政年份:
    2020
  • 资助金额:
    $ 23.33万
  • 项目类别:

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