Role and regulation of Metalloproteinase-9 in the intestine

金属蛋白酶9在肠道中的作用和调节

• 批准号: 8018896
• 负责人: SHANTHI Vasudevan SITARAMAN
• 金额: $ 5.04万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-26 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018896
• 关键词: Adherens Junction; Adhesions; Adult; Adverse effects; Americas; Ascaridil; Cell Differentiation process; Cells; Cleaved cell; Clinical; Colitis; Colon; Data; Deletion Mutation; Disease; E-Cadherin; Endopeptidases; Epithelial; Epithelial Cells; Extracellular Matrix; Extracellular Matrix Degradation; Family; Foundations; Funding; Gastroenterology; Gelatinase B; Generations; Genus Cola; Human; IL6 Signaling Pathway; Immune; Impaired wound healing; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Injury; Interleukin-6; Intestines; Matrix Metalloproteinases; Mediating; Membrane; Metalloproteases; Morbidity - disease rate; Mus; Pathogenesis; Pathologic Processes; Peptide Hydrolases; Physiological; Play; Proteins; Regulation; Role; Signal Pathway; Site; Source; TNF gene; Therapeutic; Tissues; Wound Healing; base; clinically relevant; design; extracellular; in vitro Model; in vivo; insight; knock-down; large bowel Crohn' s disease; member; mortality; notch protein; overexpression; prevent

The Metalloproteinases (MMP) are a family of Zn-dependent endopeptidases involved in a variety of physiological and pathological processes that require extracellular matrix degradation or protelytic activation such as wound healing, differentiation and inflammatory cell infiltration. MMP-9 is a secreted MMP considered to be a vital member of this protease family. MMP-9 is absent from normal adult intestine and colon but is highly upregulated during experimental colitis and human inflammatory bowel disease (IBD). Remarkably, up to this point, the regulation and function of MMP-9 in the intestine has not been studied. We demonstrated that epithelial cell-derived MMP-9 mediates tissue damage during intestinal inflammation. In addition to its role in inflammation, our data demonstrate that MMP-9 plays an important role in intestinal epithelial cell differentiation. This proposal is based upon an exciting hypothesis that will predict the physiological function of MMP-9 and provide insight into the pathophysiological and potentially clinically relevant consequence of MMP-9 expression. We hypthesize that i) the regulated expression of MMP-9 during intestinal cell differentiation plays a role in cell fate determination ii) the aberrant expression of MMP-9 during disease state mediates tissue injury by impairing cell-cell and cell-ECM interaction. Thus the objectives of this proposal are to examine the regulation and function of MMP-9 expression in intestinal epithelial cell differentiation (specific aim 1) and during colitis (specific aim 2 and 3). Taken together, our studies will not only elucidate the function, regulation and mechanism of action of MMP-9, but also provide a basis for MMP-9 targeted therapies that could be used in the clinical setting to prevent consequences of intestinal inflammation. Inflammatory diseases of the bowel are a cause of significant morbidity and mortality in U.S. The pathogenesis of inflammatory bowel disease is not known and current therapeutic strategies are sub-optimal and associated with significant side effects. This proposal will elucidate the function, regulation and mechanism of action of metalloproteinase-9, a protease that is highly upregulated during colitis. Importantly, information gained from this project will be instrumental for the generation of new strategies aimed at preventing and/or treating intestinal inflammation.

金属蛋白酶（MMP）是参与Zn依赖性内肽酶的家族 需要细胞外基质的各种生理和病理过程 降解或公共激活，例如伤口愈合，分化和 炎症细胞浸润。 MMP-9是一个分泌的MMP，被认为是重要的成员 这个蛋白酶家族。 MMP-9不含正常的成人肠和结肠，但 实验性结肠炎和人类炎症性肠病期间高度上调 （IBD）。值得注意的是，到目前为止，MMP-9在肠中的调节和功能 尚未研究。我们证明了上皮细胞衍生的MMP-9介导 肠道炎症期间的组织损伤。除了它在炎症中的作用，我们的 数据表明，MMP-9在肠上皮细胞中起重要作用 分化。该提议基于一个令人兴奋的假设，该假设将预测 MMP-9的生理功能，并洞悉病理生理和 MMP-9表达的潜在临床相关后果。我们夸大了我） 肠细胞分化过程中MMP-9的调节表达在细胞中起作用 命运确定ii）疾病状态中MMP-9的异常表达 通过损害细胞细胞和细胞ECM相互作用来损伤组织损伤。因此，目标的目标 建议是检查MMP-9表达在肠道中的调节和功能 上皮细胞分化（特定目标1）和结肠炎期间（特定目标2和3）。 综上所述，我们的研究不仅会阐明功能，调节和 MMP-9的作用机理，但也为MMP-9靶向疗法提供了基础 可以在临床环境中使用，以防止肠的后果 炎。肠道炎症性疾病是导致发病率明显和死亡率的原因 美国，炎症性肠病的发病机理尚不清楚，目前 治疗策略是最佳的，并且与显着的副作用相关。这 提案将阐明功能，调节和作用机理 金属蛋白酶9，一种在结肠炎期间高度上调的蛋白酶。重要的是， 从这个项目中获得的信息将有助于新的 旨在防止和/或治疗肠炎的策略。