Role and regulation of Metalloproteinase-9 in the intestine

描述(申请人提供)：金属蛋白酶(MMPs)是一个依赖锌的内肽酶家族，参与各种生理和病理过程，需要细胞外基质降解或蛋白水解酶激活，如伤口愈合、分化和炎症细胞浸润。基质金属蛋白酶-9是一种分泌型基质金属蛋白酶，被认为是该蛋白水解酶家族的重要成员。基质金属蛋白酶-9在正常成人肠道和结肠中缺失，但在实验性结肠炎和人类炎症性肠病(IBD)中高度上调。值得注意的是，到目前为止，还没有人研究基质金属蛋白酶-9在肠道中的调节和作用。我们证明了上皮细胞来源的基质金属蛋白酶-9在肠道炎症过程中介导了组织损伤。除了在炎症中的作用外，我们的数据还表明，基质金属蛋白酶-9在肠上皮细胞分化中起着重要作用。这一建议是基于一个令人兴奋的假说，该假说将预测基质金属蛋白酶-9的生理功能，并提供对基质金属蛋白酶-9表达的病理生理和潜在的临床相关后果的洞察。我们推测：1)在肠道细胞分化过程中，基质金属蛋白酶-9的表达调控在决定细胞命运中起作用；2)在疾病状态下，基质金属蛋白酶-9的异常表达通过损害细胞-细胞和细胞-细胞外基质之间的相互作用来介导组织损伤。因此，本研究的目的是研究基质金属蛋白酶-9在肠上皮细胞分化(特异性目标1)和结肠炎(特异性目标2和3)中表达的调节和作用。综上所述，我们的研究不仅将阐明基质金属蛋白酶-9的功能、调控和作用机制，而且还将为临床应用基质金属蛋白酶-9的靶向治疗以预防肠道炎症的后果提供依据。公共卫生相关性：在美国，肠炎性疾病是导致严重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，目前的治疗策略不是最优的，而且与显著的副作用相关。这项建议将阐明金属蛋白酶-9的功能、调节和作用机制，这是一种在结肠炎过程中高度上调的蛋白酶。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战略。

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.