Apical Polarity Complex Signaling in Inflammation in Intestinal Epithelia

肠上皮炎症中的顶端极性复合信号传导

• 批准号: 8371947
• 负责人: Pedro Salas
• 金额: $ 33.28万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8371947
• 关键词: Affect; American; Animal Model; Antibodies; Apical; Cell Line; Cell Polarity; Cell physiology; Cells; Chronic; Colitis; Colorectal; Complex; Data; Defect; Disease; Down-Regulation; Epithelial; Epithelial Cells; Epithelium; Event; Experimental Models; Feedback; Funding; Immune system; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intervention; Intestines; Knowledge; Laboratories; Modeling; Molecular; Mus; Myosin Light Chain Kinase; NFKB Signaling Pathway; Natural Immunity; Nonmuscle Myosin Type IIA; Pathogenesis; Pathway interactions; Patients; Peptides; Permeability; Play; Publishing; Reporting; Risk; Role; Signal Pathway; Signal Transduction; Staging; Structure; TNF gene; Testing; Therapeutic; Tight Junctions; Tissues; Trefoil; Tumor Necrosis Factor Receptor; Work; cytokine; economic impact; in vivo; insight; intervention effect; intestinal epithelium; non-muscle myosin; novel; preconditioning; research study; response; therapeutic target; wound

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. PUBLIC HEALTH RELEVANCE: Inflammatory Bowel Disease is a multi-factorial aberrant response of the immune system that, among other effects, impacts on the layer of cells lining the intestinal lumen, the epithelium. This project studies a novel intracellular signaling pathway in the epithelium that counteracts the effects of inflammation. Importantly, if our hypothesis is correct, inhibition of this new pathway may contribute to the persistence of the effects of inflammation and may provide new unsuspected therapeutic opportunities.

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，在小鼠结肠炎DSS模型和炎症性肠病患者中，肠上皮细胞中的非典型PKC显著下调。 在本项目中，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器的影响，已知这些效应器在这些细胞中IBD的病理生理学中至关重要。我们的初步数据有力地表明，在动物模型和患者中观察到的aPKC活性降低，足以触发经典I？B途径独立于TNFR。 这一观察结果开启了这样的可能性，即aPKC下游的信号传导可以建立负反馈，即使去除原始细胞因子刺激，该负反馈也使上皮细胞保持“发炎”状态。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分泌细胞因子，这在慢性肠道炎症中是可取的。 此外，由于这些途径对上皮细胞是特异性的，因此了解它们可以允许组织特异性干预。 这一现象的机制方面和后果将在目标1中研究。我们的初步数据还表明，类似的短暂事件发生在上皮伤口中，这表明它也可能参与上皮恢复的早期阶段，这将在目标2中进行B检验。 最后，将在目标3中的结肠炎动物模型的背景下分析目标1和2中研究的分子机制。 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，因为你想不到的可能的治疗靶点，以调节上皮细胞对炎症的反应。 公共卫生相关性：炎症性肠病是免疫系统的一种多因素异常反应，除了其他影响外，还影响肠腔衬里的细胞层，即上皮细胞。该项目研究了一种新的细胞内信号通路在上皮细胞，抵消炎症的影响。 重要的是，如果我们的假设是正确的，抑制这一新途径可能有助于炎症效应的持续存在，并可能提供新的意想不到的治疗机会。