Role and regulation of Metalloproteinase-9 in the intestine

描述（由申请人提供）：金属蛋白酶（MMP）是锌依赖的内肽酶家族，参与多种需要细胞外基质降解或蛋白水解激活的生理和病理过程，如伤口愈合、分化和炎症细胞浸润。MMP-9是一种分泌性MMP，被认为是该蛋白酶家族的重要成员。MMP-9在正常成人肠道和结肠中不存在，但在实验性结肠炎和人类炎症性肠病（IBD）中表达高度上调。值得注意的是，到目前为止，还没有研究MMP-9在肠道中的调节和功能。我们证明上皮细胞来源的MMP-9介导肠道炎症期间的组织损伤。除了在炎症中发挥作用外，我们的数据还表明MMP-9在肠上皮细胞分化中发挥重要作用。该建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，并为MMP-9表达的病理生理和潜在的临床相关后果提供见解。我们假设i)肠细胞分化过程中MMP-9的调控表达在细胞命运决定中起作用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相互作用介导组织损伤。因此，本提案的目的是研究肠上皮细胞分化（特异性目的1）和结肠炎（特异性目的2和3）期间MMP-9表达的调节和功能。综上所述，我们的研究不仅可以阐明MMP-9的功能、调控和作用机制，还可以为临床应用MMP-9靶向治疗提供依据，预防肠道炎症的后果。公共卫生相关性：肠道炎症性疾病是美国重要的发病率和死亡率的原因之一。炎症性肠病的发病机制尚不清楚，目前的治疗策略是次优的，并伴有明显的副作用。本研究旨在阐明在结肠炎中高度上调的蛋白酶金属蛋白酶-9的功能、调控和作用机制。重要的是，从该项目中获得的信息将有助于制定旨在预防和/或治疗肠道炎症的新策略。

DESCRIPTION (provided by applicant): 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 proteolytic 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 hypothesize 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. PUBLIC HEALTH RELEVANCE: 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.