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Interleukin-1 Beta Modulation of Intestinal Tight Junction Barrier

Interleukin-1 Beta 调节肠道紧密连接屏障

基本信息

批准号：
8290490
负责人：
THOMAS Y MA
金额：
$ 31.98万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8290490
关键词：
Antigens Applications Grants Biological Models Biological Preservation Crohn&apos s disease Data Defect Development Disease Down-Regulation Epithelial Epithelial Cells Functional disorder Gastrointestinal tract structure Gene Expression Genes Health In Vitro Inflammation Inflammation Process Inflammatory Inflammatory disease of the intestine Interleukin-1 Interleukin-1 beta Interleukins Intestines Laboratories Lead Left Mediating Messenger RNA MicroRNAs Mitogen-Activated Protein Kinases Molecular Mus Myosin Light Chain Kinase Nuclear Pathway interactions Patients Perfusion Permeability Play Process Proteins Regulation Role Side Signal Pathway Signal Transduction Suggestion Testing Therapeutic Therapeutic Agents Tight Junctions Time Treatment Efficacy Up-Regulation base clinically relevant cytokine in vivo in vivo Model mRNA Expression monolayer mouse model novel novel therapeutics occludin prevent protein expression response therapeutic target transcription factor

项目摘要

DESCRIPTION (provided by applicant): Patients with Crohn's disease (CD) have a defective intestinal tight junction (TJ) barrier, manifested by an increase in intestinal paracellular permeability. The defective intestinal TJ barrier is an important pathogenic factor of CD that allows increased paracellular permeation of toxic luminal antigens, leading to intestinal inflammation. Interleukin-1( (IL-1(), a prototypical multi-functional pro-inflammatory cytokine, has been shown to play a central role in the intestinal inflammation process in the gastrointestinal tract. Recent studies indicate that an important pro-inflammatory action of IL-1( and other pro-inflammatory cytokines is to cause a functional opening of the intestinal TJ barrier, leading to an increase in paracellular permeability. The broad objectives of this grant application are to elucidate the cellular and molecular mechanisms that mediate the IL-1( induced increase in intestinal TJ permeability and to identify potential therapeutic targets to prevent the IL-1( induced increase in intestinal TJ permeability and subsequent development of intestinal inflammation, using an in-vitro (consisting of filter-grown Caco-2 intestinal epithelial monolayers) and a newly developed in-vivo mouse model system. Deciphering the intracellular pathways and the molecular mechanisms involved in IL-1( modulation of intestinal TJ barrier function has great potential scientific and clinical relevance in advancing novel scientific concepts regarding intestinal TJ barrier dysfunction during inflammation and for developing new therapeutic strategies that target the TJ barrier in preventing intestinal inflammation. Our preliminary studies suggested that the IL-1( induced increase in intestinal epithelial TJ permeability was mediated in part by: 1) activation of extracellular signal- regulated kinases 1 and 2 (ERK1/2) signaling cascade; 2) activation of myosin light chain kinase (MLCK) gene; and 3) microRNA (miRNA) induced degradation of occludin mRNA. Based on our preliminary data, we hypothesize that the IL-1( induced increase in intestinal TJ permeability is regulated in part by ERK1/2 signaling cascade induced activation of MLCK gene and subsequent increase in MLCK protein expression and by microRNA induced degradation of occludin mRNA and depletion of occludin protein. The proposed specific aims of this grant application are to: 1) delineate the intracellular signaling cascade and the molecular processes that mediate the IL-1( induced increase in intestinal TJ permeability; 2) delineate the cellular and molecular mechanisms that mediate the IL-1( induced down-regulation of occludin gene and protein expression; and 3) delineate the mechanisms that mediate the IL-1( induced increase in intestinal permeability in-vivo and the therapeutic implications of preservation of intestinal TJ barrier function in-vivo. PUBLIC HEALTH RELEVANCE: Patients with Crohn's disease have a leaky gut, characterized by an increase in intestinal permeability to harmful antigens in the intestinal lumen. The studies proposed in this grant application seek to determine the intracellular and molecular processes that contribute to the leaky gut of Crohn's disease. Interleukin-1( has been shown to play an important role in promoting intestinal inflammation in Crohn's disease and other inflammatory conditions of the gut. The focus of these studies will be to delineate the intracellular and molecular processes that mediate the interleukin-1( induced disturbance of intestinal barrier function. The proposed studies also seek to identify potential therapeutic targets and strategies to induce therapeutic re-tightening or normalization of leaky gut in Crohn's disease.

描述(申请人提供)：克罗恩病(CD)患者存在肠道紧密连接(TJ)屏障缺陷，表现为肠道细胞旁通透性增加。肠道TJ屏障的缺陷是CD的一个重要致病因素，它允许有毒管腔抗原在细胞旁的渗透增加，从而导致肠道炎症。白介素1(IL-1)是一种典型的多功能促炎细胞因子，已被证明在胃肠道炎症过程中发挥核心作用。最近的研究表明，IL-1(和其他促炎细胞因子)的一个重要的促炎作用是引起肠道TJ屏障的功能性开放，导致细胞旁通透性增加。这项赠款申请的广泛目标是阐明介导IL-1(诱导肠道TJ通透性增加)的细胞和分子机制，并利用体外(由过滤生长的Caco-2肠道上皮单分子层组成)和新开发的体内小鼠模型系统，确定防止IL-1(诱导肠道TJ通透性增加和随后发展的肠道炎症)的潜在治疗靶点。破译IL-1(调节肠道TJ屏障功能)所涉及的细胞内途径和分子机制，对于提出有关炎症时肠道TJ屏障功能障碍的新科学概念以及开发针对TJ屏障预防肠道炎症的新的治疗策略具有重要的潜在的科学和临床意义。我们的初步研究表明，IL-1诱导肠上皮细胞通透性增加的部分原因是：1)细胞外信号调节激酶1和2(ERK1/2)信号转导通路的激活；2)肌球蛋白轻链激酶(MLCK)基因的激活；3)microRNA(MiRNA)诱导occludin mRNA的降解。根据我们的初步数据，我们假设IL-1诱导的肠道TJ通透性增加部分是通过ERK1/2信号通路诱导MLCK基因的激活和随后MLCK蛋白表达的增加以及通过microRNA诱导occludin mRNA的降解和occludin蛋白的耗竭来调节的。这项赠款申请的拟议具体目的是：1)描述细胞内信号转导通路和介导IL-1(诱导肠道TJ通透性增加)的分子过程；2)描述介导IL-1(诱导阻滞素基因和蛋白表达下调)的细胞和分子机制；以及3)描述介导IL-1(诱导体内肠道通透性增加)的机制以及体内保留肠道TJ屏障功能的治疗意义。与公共卫生相关：克罗恩病患者有肠道渗漏，其特征是肠道对肠腔内有害抗原的渗透性增加。在这项拨款申请中提出的研究试图确定导致克罗恩病肠道渗漏的细胞内和分子过程。白介素1(IL-1)已被证明在促进克罗恩病和其他肠道炎症条件下的肠道炎症中发挥重要作用。这些研究的重点将是描绘介导白细胞介素1(诱导肠屏障功能障碍)的细胞内和分子过程。拟议的研究还试图确定潜在的治疗目标和策略，以诱导克罗恩病渗漏肠道的治疗重新收紧或正常化。