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Regulation of Paracellular Permeability by IFNgamma and TNFa

IFNγ 和 TNFa 对细胞旁通透性的调节

基本信息

批准号：
7460826
负责人：
JERROLD R. TURNER
金额：
$ 33.3万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7460826
关键词：
Actomyosin Biochemical Cells Characteristics Clinical Crohn&apos s disease Cytoskeletal Modeling Data Development Disease Disruption Enteral Epithelial Event Figs - dietary Foundations Functional disorder Future Goals Health Human Image Immune In Situ In Vitro Infection Inflammatory Interferon Type II Interferons Intestinal Diseases Intestines Knockout Mice Lamina Propria Lead Light MYLK gene Mediating Medical Modality Molecular Mus Myosin Light Chain Kinase Myosin Light Chains Myosin Type II Oligopeptides Pathogenesis Permeability Phosphorylation Process Protein Dynamics Proteins Regulation Relative (related person)Reperfusion Injury Research Research Personnel Resistance Role Signal Transduction Structure T-Cell Activation TNFRSF1A gene TNFRSF1B gene Testing Therapeutic Therapeutic Effect Tight Junctions Time Transcriptional Regulation Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha Tumor Necrosis Factors Up-Regulation Wild Type Mouse absorption base cytokine experience graft vs host disease human TNF protein human disease in vivo inhibitor/antagonist innovation intestinal epithelium kinase inhibitor loss of function novel prevent programs protein distribution receptor expression restoration success

项目摘要

DESCRIPTION (provided by applicant): Loss of epithelial barrier function is characteristic of inflammatory, infectious, ischemic, and immune mediated intestinal diseases. Synergistic signaling between the TH1 cytokines interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha), which are frequently elevated in these diseases, has been implicated in this barrier dysfunction. In turn, compromised barrier function can allow noxious nominal material to access the lamina propria, stimulate immune cells, and augment IFNgamma and TNFalpha release, culminating in a self-amplifying cycle of epithelial dysfunction. In vivo data show that barrier dysfunction can be reversed by anti-TNF a therapies. We have recently shown that IFN gamma / TNFalpha -induced loss of barrier function is related to increased myosin light chain (MLC) phosphorylation and that both loss of barrier function and increased MLC phosphorylation can be reversed by a novel oligopeptide MLC kinase inhibitor. Despite this, the mechanisms by which IFNgamma / TNFalpha increase MLC phosphorylation and decrease barrier function are not well understood. Characterization of these regulatory mechanisms is important to understanding the pathogenesis of diverse intestinal diseases and may also identify novel targets for therapy of IFNgamma / TNFalpha -driven intestinal disease. This may lead to the development of effective non-immunosuppresive therapies for diseases such as Crohn's disease, enteric infection, ischemia-reperfusion injury, and graft versus host disease. The central hypothesis of this proposal is that IFNgamma and TNFalpha synergize to activate a signaling cascade that results in increased TNF receptor expression, increased MLC kinase expression, increased MLC phosphorylation, tight junction reorganization, and epithelial barrier dysfunction. The aims of this application are to test this hypothesis by i) determining the role of IFNgamma in enhancing epithelial responsiveness to TNFalpha and the mechanisms by which IFNgamma and TNalpha synergize to increase MLC phosphorylation, ii) defining the effects of IFNgamma and TNFalpha on tight junction protein dynamics using integrated functional, biochemical, and real time imaging approaches, and iii) exploring the effects of IFNgamma and TNFalpha on the regulation of MLC phosphorylation in vivo using knockout mice and pharmacologic agents that prevent IFNgamma / TNFalpha -induced barrier dysfunction in vitro. We expect that these studies will have significant positive effects on human health because they will lead to the development of new understanding of the mechanisms by which barrier function is compromised in disease and will provide the foundation necessary for the development of strategies for enhancement of barrier function as a therapeutic modality.