Matrilysin regulation in colonic epithelial cells and role in barrier function

结肠上皮细胞中基质溶素的调节及其在屏障功能中的作用

• 批准号: 7497481
• 负责人: JOHN KWON
• 金额: $ 15.58万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-20 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7497481
• 关键词: Acute; Address; Adherence; Adherens Junction; Adhesions; Animal Model; Apical; Bacteroides fragilis; Basement membrane; Binding; Cell Adhesion; Cell Communication; Cell Line; Cells; Cessation of life; Chronic; Chronic Disease; Cleaved cell; Colitis; Complex; Data; Defect; Desmosomes; Diagnosis; E-Cadherin; Epithelial; Epithelial Cells; Gene Expression; Genetic Transcription; Homeostasis; Indium; Infection; Inflammatory; Inflammatory Bowel Diseases; Integrin Binding; Intestines; Knockout Mice; Laboratories; Maintenance; Matrilysin; Matrix Metalloproteinases; Modeling; Mus; NF-kappa B; Pathogenesis; Patients; Permeability; Play; Production; Proteins; Regulation; Research Personnel; Resistance; Rest; Role; Sodium Dextran Sulfate; Testing; Tight Junctions; Toxin; Tumor Necrosis Factor-alpha; United States; Work; Wound Healing; cytokine; extracellular; foodborne; mRNA Expression; pathogen; programs; response; tissue culture

DESCRIPTION (provided by applicant): The epithelial lining of the intestine forms a protective barrier which separates the luminal contents from the rest of the intestine. The integrity of the intestinal barrier is dependant upon the maintenance of the epithelial cell interactions with apical junctional complexes and the underlying basement membrane. These interactions have been shown to be compromised in intestinal infections as well as in chronic inflammatory states, such as inflammatory bowel disease. Previous work by other laboratories demonstrate [sic] the intestinal barrier function can be altered by inflammatory cytokines, as shown by decreases in transepithelial resistance. The exact mechanism by which these inflammatory cytokines influence the intestinal barrier is unknown. Our preliminary data implicates matrix metalloproteinase-7 (matrilysin) in the pathogenesis of inflammatory cytokine-induced altered barrier resistance. Matrilysin gene transcription as well as protein production, secretion and activation are increased in response to inflammatory cytokines. Basolateral treatment with activated matrilysin results in increased barrier permeability in cultured colonic epithelial cell lines. Our hypothesis is that matrilysin influences colonic epithelial barrer [sic] function through cleaving basolaterally-located apical junction complex proteins and disrupting basement membrane adherence and its regulation by inflammatory cytokines plays a role in the onset of acute and chronic colitis. Three specific aims will address the above hypothesis. First, we will elucidate the mechanism by which matrilysin regulates the shedding of extracellular components of apical junctional complex proteins and basement membrane adhesion proteins. Second, we will examine the inflammatory cytokine-induced regulation of matrilysin transcription. Third, we will determine whether matrilysin plays a key role in the onset of murine models of inflammatory bowel disease and infectious colitis. These studies will increase our understanding of the mechanism by which the intestinal epithelial cells maintain the barrier protecting the intestine from luminal contents both in tissue culture models and animal models of wound healing, infectious colitis and inflammatory bowel disease. These studies will also determine the mechanisms by which inflammatory cytokines regulate matrilysin gene expression.

描述（由申请人提供）： 肠的上皮内层形成保护屏障，将管腔内容物与肠的其余部分分开。肠屏障的完整性取决于上皮细胞与顶端连接复合物和下面的基底膜相互作用的维持。这些相互作用已被证明在肠道感染以及慢性炎症状态（例如炎症性肠病）中受到损害。其他实验室之前的工作表明，炎症细胞因子可以改变肠道屏障功能，如跨上皮阻力的降低所示。这些炎症细胞因子影响肠道屏障的确切机制尚不清楚。我们的初步数据表明基质金属蛋白酶 7（matrilysin）参与炎症细胞因子诱导的屏障抵抗力改变的发病机制。基质溶解素基因转录以及蛋白质产生、分泌和激活都会因炎症细胞因子的反应而增加。用活化的基质溶解素进行基底外侧处理会导致培养的结肠上皮细胞系的屏障通透性增加。我们的假设是，基质溶解素通过裂解位于基底外侧的顶端连接复合物蛋白并破坏基底膜粘附来影响结肠上皮屏障[原文如此]功能，并且炎症细胞因子对其的调节在急性和慢性结肠炎的发作中发挥作用。三个具体目标将解决上述假设。首先，我们将阐明基质溶解素调节顶端连接复合物蛋白和基底膜粘附蛋白的细胞外成分脱落的机制。其次，我们将检查炎症细胞因子诱导的基质溶解素转录调节。第三，我们将确定基质溶解素是否在炎症性肠病和传染性结肠炎的小鼠模型的发病中发挥关键作用。这些研究将加深我们对肠上皮细胞在伤口愈合、感染性结肠炎和炎症性肠病的组织培养模型和动物模型中维持保护肠道免受管腔内容物侵害的屏障机制的理解。这些研究还将确定炎症细胞因子调节基质溶解素基因表达的机制。