ADAM-mediated Shedding in Endothelial Inflammatory Responses

描述（由申请人提供）：炎症反应中ADAM介导的脱落炎症是疾病发病机制中的关键过程，白细胞募集和经内皮迁移到发炎组织中控制急性和慢性炎症性疾病的发生和进展。由R 01资助的研究表明，由两种跨膜蛋白酶Adam 10和Adam 17介导的蛋白水解控制炎症反应。我们的数据特别涉及（i）单核细胞Adam 10在体内限制单核细胞迁移到发炎的血管;（ii）中性粒细胞Adam 17在体内通过切割L-选择素限制早期中性粒细胞流入炎症部位;（iii）单核细胞Adam 17在体外促进单核细胞在内皮细胞之间的渗出，以及（iv）巨噬细胞Adam 17在促进炎症消退。我们的总体假设是，细胞，底物，和内容特异性切割的关键炎症蛋白的Adam 10和Adam 17是至关重要的炎症反应的调节。拟议的研究将建立在这些观察的基础上，确定：1）跨膜蛋白酶Adam 10和Adam 17调节炎症反应的体外和体内机制; 2）建立Adam 10和Adam 17负责调节单核细胞进出炎症部位的底物。这些研究有可能确定生物标志物，以识别患有慢性炎症性疾病的风险患者，并帮助确定治疗策略。

DESCRIPTION (provided by applicant): ADAM-mediated Shedding in Inflammatory Responses Inflammation is a key process in disease pathogenesis, and leukocyte recruitment and transendothelial migration into inflamed tissues control both initiation and progression of acute and chronic inflammatory diseases. Studies funded by this R01 have demonstrated that proteolysis mediated by two transmembrane proteases, Adam10 and Adam17, controls the inflammatory response. Our data specifically implicate (i) monocyte Adam10 in limiting monocyte emigration into inflamed vessels in vivo; (ii) neutrophil Adam17 in limiting early neutrophil influx into inflammatory sites in vivo through its cleavage of L-selectin; (iii) monocyt Adam17 in promoting monocyte diapedesis between endothelial cells in vitro, and (iv) macrophage Adam17 in promoting the resolution of inflammation. Our overall hypothesis is that cell-, substrate-, and contect-specific cleavage of key inflammatory proteins by Adam10 and Adam17 is critical to regulation of inflammatory responses. The proposed studies will build upon these observations by determining: 1) the in vitro and in vivo mechanisms by which the transmembrane proteases Adam10 and Adam17 modulate inflammatory responses; and 2) establish substrates of Adam10 and Adam17 responsible for regulation monocyte trafficking into and out of inflammatory sites. These studies have the potential to identify biomarkers to recognize patients at risk with chronic inflammatory diseases, and to help determine therapeutic strategies for their treatment.