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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（由申请人提供）：克罗恩病（CD）患者肠道紧密连接（TJ）屏障有缺陷，表现为肠道细胞旁通透性增加。有缺陷的肠道TJ屏障是CD的一个重要致病因素，它允许毒性腔抗原增加细胞旁渗透，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TJ屏障的功能性开放，导致细胞旁通透性增加。本资助申请的主要目的是阐明介导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（由过滤器培养的Caco-2肠上皮单层组成）和新开发的体内小鼠模型系统，确定潜在的治疗靶点，以防止IL-1(诱导的肠道TJ通透性增加和随后的肠道炎症发展。揭示IL-1调节肠道TJ屏障功能的细胞内通路和分子机制，对于推进炎症期间肠道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治疗策略具有重要的科学和临床意义。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：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TJ通透性增加部分受ERK1/2信号级联诱导的MLCK基因激活和随后MLCK蛋白表达增加以及microRNA诱导的occludin mRNA降解和occludin蛋白消耗的调节。该资助申请的具体目的是：1)描述介导IL-1诱导的肠道TJ通透性增加的细胞内信号级联和分子过程；2)描述介导IL-1诱导的occludin基因和蛋白表达下调的细胞和分子机制；3)阐明IL-1诱导的体内肠道通透性增加的机制，以及维持体内肠道TJ屏障功能的治疗意义。公共卫生相关性：克罗恩病患者有漏肠，其特征是肠道对肠腔中有害抗原的渗透性增加。本拨款申请中提出的研究旨在确定导致克罗恩病漏肠的细胞内和分子过程。白细胞介素-1(已被证明在克罗恩病和其他肠道炎症中促进肠道炎症发挥重要作用。这些研究的重点将是描述介导白细胞介素-1诱导的肠屏障功能紊乱的细胞内和分子过程。拟议的研究还寻求确定潜在的治疗靶点和策略，以诱导克罗恩病中漏肠的治疗性再收紧或正常化。