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: 8495319
• 负责人: Pedro Salas
• 金额: $ 32.11万
• 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/8495319
• 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; 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.

描述（应用程序提供）：在我们的实验室中，最近发表的工作表明，在TNF刺激下，鼠类结肠炎的DSS模型和炎症性肠病患者中，肠上皮细胞中非典型PKC的下调深度下调。在该项目中，我们将机械分析APKC丢失对细胞功能，信号通路和分子效应的后果，已知在这些细胞中IBD的病理生理学中至关重要。我们的初步数据强烈表明，与动物模型和患者中观察到的APKC活性的降低相当，足以触发经典的I？B途径的激活，独立于TNFR。该观察结果开启了APKC下游信号传导可能会建立负反馈，即使去除原始的细胞因子刺激剂，也可以使上皮细胞处于“发炎”状态。如果我们的假设是正确的，那么打破此循环可能有助于迅速纠正上皮细胞的屏障缺陷和细胞因子分泌，这在慢性肠炎中是可取的。此外，由于这些途径特定于上皮细胞，因此可以理解它们可能允许组织特定的干预措施。这种现象的机理方面和后果将在目标1中进行研究。我们的初步数据还表明，类似的瞬态事件发生在上皮伤口中，这表明假设可能在上皮限制的早期阶段也可能涉及上皮限制的早期阶段。总共有望建立一个完全新颖的信号通路，确定其正常功能并带来新的功能，因为YE无规律的可能的治疗靶标，以调节上皮反应对炎症。