Interleukin-1 Beta Modulation of Intestinal Tight Junction Barrier

Interleukin-1 Beta 调节肠道紧密连接屏障

• 批准号: 7806656
• 负责人: THOMAS Y MA
• 金额: $ 35.64万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7806656
• 关键词: Antigens; Applications Grants; Biological Models; Biological Preservation; Crohn' s disease; Data; Defect; Development; Disease; Down-Regulation; Epithelial; Epithelial Cells; Functional disorder; Gastrointestinal tract structure; Gene Expression; Gene Proteins; Genes; In Vitro; Inflammation; Inflammation Process; Inflammatory; Inflammatory disease of the intestine; Interleukin-1; Interleukin-1 alpha; Interleukin-1 beta; Interleukins; Intestines; Laboratories; Lead; Left; Mediating; Messenger RNA; MicroRNAs; Mitogen-Activated Protein Kinase 3; 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; public health relevance; response; therapeutic target; transcription factor

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）患者的肠紧密连接（TJ）屏障有缺陷，这表现为肠道副细胞渗透性的增加。有缺陷的肠道TJ屏障是CD的重要致病因素，它允许增加毒性腔抗原的细胞细胞细胞渗透，从而导致肠炎。肠介菌1（（IL-1（）是一种原型多功能性促炎性细胞因子，已显示出在胃肠道的肠道炎症过程中起着核心作用渗透性。该赠款应用的广泛目标是阐明介导IL-1的细胞和分子机制（诱导的肠道TJ渗透性的增加，并确定潜在的治疗靶标，以防止肠道TJ TJ TJ诱导的促进性和随后的肠道体积的增长（单层）和新开发的体内小鼠模型系统。我们的初步研究表明，IL-1（诱导的肠上皮TJ渗透率的增加部分是通过以下方式介导的：1）激活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）诱导的闭合蛋白mRNA降解。 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体内和维护肠道屏障功能的治疗意义。该赠款申请中提出的研究旨在确定有助于克罗恩病渗漏的细胞内和分子过程。白介素-1（已显示在促进克罗恩病和肠道的其他炎症状况方面起着重要作用。这些研究的重点将是描述细胞内和分子过程，这些过程介导了肠道内核酸1的介导肠道障碍（诱导的肠道障碍），以寻求肠道障碍。还可以识别出可能的策略或策略，以识别策略的范围，以实现策略，以实现策略的作用。克罗恩氏病的肠道漏水。