Apical Polarity Complex Signaling in Inflammation in Intestinal Epithelia

描述（由申请人提供）：我们实验室最近发表的研究表明，在TNF -刺激下，小鼠结肠炎DSS模型和炎症性肠病患者中，肠上皮细胞中的非典型PKC深度下调。在这个项目中，我们将从机制上分析aPKC缺失对细胞功能、信号通路和分子效应物的影响，这些已知在这些细胞的IBD病理生理中是必不可少的。我们的初步数据强烈表明，aPKC活性的下降与在动物模型和患者中观察到的相比，足以触发经典I？B通路独立于TNFR。这一观察结果开启了一种可能性，即aPKC下游的信号可能建立了一个负反馈，使上皮细胞处于“炎症”状态，即使原始的细胞因子刺激被移除。如果我们的假设是正确的，打破这个循环可能有助于快速纠正屏障缺陷和上皮细胞的细胞因子分泌，这在慢性肠道炎症中是可取的。此外，由于这些通路对上皮细胞是特异性的，了解它们可能有助于组织特异性干预。机制方面和这一现象的后果将在Aim 1研究。我们的初步数据还表明，类似的短暂事件也发生在上皮伤口中，这表明它可能也参与了上皮恢复的早期阶段，这将在Aim 2中进行验证。最后，aims 1和2中研究的分子机制将在aims 3中结肠炎动物模型的背景下进行分析。总的来说，该项目有望建立一个全新的信号通路，确定其正常功能，并带来新的，因为我们从未预料到的可能的治疗靶点来调节上皮对炎症的反应。

DESCRIPTION (provided by applicant): Recent published work in our laboratory has shown a profound downregulation of atypical PKC in intestinal epithelial cells under TNF¿ stimulation, in the DSS model of murine colitis, and in Inflammatory Bowel Disease patients. In this project we will analyze mechanistically the consequences of aPKC loss on cellular functions, signaling pathways, and molecular effectors, known to be essential in the pathophysiological of IBD in these cells. Our preliminary data strongly indicate that a decrease in aPKC activity comparable to that observed in the animal model and in patients, is sufficient to trigger activation of the classic I?B pathway independently of TNFR. This observation opens the possibility that signaling downstream of aPKC may establish a negative feedback that keeps epithelial cells in an "inflamed" condition even if the original cytokine stimulaton is removed. If our hypothesis is correct, breaking this cycle may help to rapidly correct barrier defects and cytokine secretion by epithelial cells, which would be desirable in chronic intestinal inflammation. Moreover, since these pathways are specific to epithelial cells, understanding them may allow tissue-specific interventions. The mechanistic aspects and the consequences of this phenomenon will be studied in Aim 1. Our preliminary data also shows that a similar transient event occurs in epithelial wounds, suggesting the hypothesis that it may also be involved in the early stages of epithelial restitution, which will b tested in Aim 2. Finally, the molecular mechanisms studied in aims 1 and 2 will be analyzed in in the context of an animal model of colitis in Aim 3. Altogether the project is expeced to establish a totally novel signaling pathway, identify its normal function, and bring new, as ye unsuspected possible therapeutic targets to modulate the epithelial response to inflammation.