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）是一个锌依赖性内肽酶家族，参与了 多种生理和病理过程需要细胞外基质 降解或蛋白水解活化，如伤口愈合、分化和 炎性细胞浸润。MMP-9是一种分泌型MMP，被认为是MMP-9的重要成员， 这个蛋白酶家族。MMP-9在正常成人肠和结肠中不存在，但在正常成人肠和结肠中不存在。 在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在肠道中的调节和功能 尚未被研究。我们证明了上皮细胞来源的MMP-9介导 肠道炎症期间的组织损伤。除了在炎症中的作用外， 结果表明，MMP-9在肠上皮细胞中起重要作用， 分化这项建议是基于一个令人兴奋的假设，将预测 MMP-9的生理功能，并提供深入了解病理生理和 MMP-9表达的潜在临床相关后果。我们推测，i） MMP-9在肠细胞分化过程中表达调节在细胞分化中发挥作用， 命运决定ii）在疾病状态期间MMP-9的异常表达介导 通过损害细胞-细胞和细胞-ECM相互作用来损伤组织。因此，这一目标 我们的研究目的是探讨MMP-9在肠上皮细胞中的表达调控和功能， 上皮细胞分化（具体目标1）和结肠炎期间（具体目标2和3）。 总之，我们的研究不仅将阐明功能，调节和 研究MMP-9的作用机制，也为MMP-9的靶向治疗提供依据 可以用于临床环境，以防止肠道疾病的后果 炎症肠道炎症性疾病是肠道疾病中显著发病率和死亡率的原因之一。 美国炎症性肠病的发病机制目前还不清楚 治疗策略是次优的并且与显著的副作用相关。这 建议将阐明功能，调节和作用机制， 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产生新的 旨在预防和/或治疗肠道炎症的策略。