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（由申请人提供）：克罗恩病（CD）患者的肠道紧密连接（TJ）屏障有缺陷，表现为肠道旁细胞通透性增加。肠道 TJ 屏障缺陷是 CD 的重要致病因素，可增加有毒管腔抗原的细胞旁渗透，导致肠道炎症。白细胞介素-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，白细胞介素-1(IL-1())具有重要的促炎作用。 IL-1（和其他促炎细胞因子）会引起肠道 TJ 屏障的功能性开放，从而导致细胞旁通透性增加。这项拨款申请的广泛目标是阐明介导 IL-1 的细胞和分子机制1(诱导增加使用体外（由过滤器生长的 Caco-2 肠上皮单层组成）和新开发的体内小鼠模型系统破译了 IL-1（肠道 TJ 屏障功能调节）的细胞内途径和分子机制，对于推进有关炎症和肠道 TJ 屏障功能障碍的新科学概念具有巨大的潜在科学和临床意义。表彰他们开发针对 TJ 屏障以预防肠道炎症的新治疗策略。我们的初步研究表明，IL-1 诱导的肠上皮 TJ 通透性增加部分是通过以下介导的：1）细胞外信号调节激酶 1 和 2 (ERK1/2) 信号级联的激活； 2）肌球蛋白轻链激酶（MLCK）基因的激活； 3) microRNA (miRNA) 诱导 occludin mRNA 降解。根据我们的初步数据，我们假设 IL-1( 诱导的肠道 TJ 通透性增加部分受到 ERK1/2 信号级联诱导的 MLCK 基因激活和随后 MLCK 蛋白表达的增加以及 microRNA 诱导的 occludin mRNA 降解的调节。该资助申请的具体目标是：1）描述细胞内信号级联和介导 IL-1（诱导肠道 TJ 增加）的分子过程。 2) 描述介导 IL-1（诱导 occludin 基因和蛋白表达下调）的细胞和分子机制；3) 描述介导 IL-1（诱导体内和肠道通透性增加）的机制。体内保留肠道 TJ 屏障功能的治疗意义公共卫生相关性：克罗恩病患者存在肠漏，其特征是肠道对肠道有害抗原的通透性增加。流明。本拨款申请中提出的研究旨在确定导致克罗恩病肠漏的细胞内和分子过程。 Interleukin-1( 已被证明在促进克罗恩病和其他肠道炎症性疾病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 interleukin-1( 诱导的干扰的细胞内和分子过程拟议的研究还试图确定潜在的治疗靶点和策略，以诱导克罗恩病漏肠的治疗重新收紧或正常化。