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

基本信息

批准号：
8131795
负责人：
JOHN KWON
金额：
$ 14.66万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
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/8131795
关键词：
Acute Address Adherence Adherens Junction Adhesions Animal Model Apical Bacteroides fragilis Basement membrane Binding Cell Adhesion Cell Communication Cell Line Cells 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 protein complex response tissue culture wound

项目摘要

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）：肠的上皮衬里形成了保护性屏障，将腔含量与肠的其余部分分开。肠壁屏障的完整性取决于上皮细胞与顶端连接络合物和基础基底膜的相互作用。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。其他实验室的先前工作证明了[SIC]肠道屏障功能可以通过炎症性细胞因子来改变，如跨二维尔电阻的降低所示。这些炎性细胞因子影响肠屏障的确切机制尚不清楚。我们的初步数据暗示了基质金属蛋白酶-7（母氏蛋白酶）在炎性细胞因子诱导的屏障抗性改变的发病机理中。响应于炎性细胞因子，母子蛋白基因转录以及蛋白质的产生，分泌和激活增加。基底外侧用活化的母系治疗导致培养的结肠上皮细胞系中的屏障渗透性增加。我们的假设是，天生蛋白通过切割基底侧面的顶端连接复合蛋白并破坏基底膜粘附及其对炎症细胞因子的调节在急性和慢性结肠炎的发作中起作用。三个具体目标将解决上述假设。首先，我们将阐明母脂蛋白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的机制。其次，我们将检查炎性细胞因子诱导的母乳蛋白转录的调节。第三，我们将确定天丽氏蛋白在炎症性肠病和感染性结肠炎的鼠模型中是否起关键作用。这些研究将提高我们对肠上皮细胞维持障碍物的机制的理解，从而保护肠道侵害肠道含量，并在组织培养模型和伤口愈合，传染性结肠炎和炎症性肠病的动物模型中免受腔内含量。这些研究还将确定炎性细胞因子调节母乳蛋白基因表达的机制。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Identification of microRNAs associated with ileal and colonic Crohn's disease.

DOI：
10.1002/ibd.21267
发表时间：
2010-10
期刊：
INFLAMMATORY BOWEL DISEASES
影响因子：
4.9
作者：
Wu, Feng;Zhang, Simin;Dassopoulos, Themistocles;Harris, Mary L.;Bayless, Theodore M.;Meltzer, Stephen J.;Brant, Steven R.;Kwon, John H.
通讯作者：
Kwon, John H.

Dynamic changes in the expression of MicroRNA-31 during inflammatory bowel disease-associated neoplastic transformation.

DOI：
10.1002/ibd.21359
发表时间：
2011-01
期刊：
INFLAMMATORY BOWEL DISEASES
影响因子：
4.9
作者：
Olaru, Alexandru V.;Selaru, Florin M.;Mori, Yuriko;Vazquez, Christine;David, Stefan;Paun, Bogdan;Cheng, Yulan;Jin, Zhe;Yang, Jian;Agarwal, Rachana;Abraham, John M.;Dassopoulos, Themistocles;Harris, Mary;Bayless, Theodore M.;Kwon, John;Harpaz, Noam;Livak, Ferenc;Meltzer, Stephen J.
通讯作者：
Meltzer, Stephen J.

Peripheral blood microRNAs distinguish active ulcerative colitis and Crohn's disease.

DOI：
10.1002/ibd.21450
发表时间：
2011-01
期刊：
INFLAMMATORY BOWEL DISEASES
影响因子：
4.9
作者：
Wu, Feng;Guo, Natalie Jia;Tian, Hongying;Marohn, Michael;Gearhart, Susan;Bayless, Theodore M.;Brant, Steven R.;Kwon, John H.
通讯作者：
Kwon, John H.