ADAM-mediated Shedding in Endothelial Inflammatory Responses

描述(申请人提供)：ADAM介导的炎症反应中的脱落炎症是疾病发病机制中的一个关键过程，白细胞在炎症组织中的募集和跨内皮细胞的迁移控制着急性和慢性炎症性疾病的开始和发展。由该R01资助的研究表明，由两种跨膜蛋白水解酶ADAM10和ADAM17介导的蛋白分解控制炎症反应。我们的数据特异地暗示：(I)单核细胞ADAM10在体内限制单核细胞向炎症血管的迁移；(Ii)中性粒细胞ADAM17通过其对L-选择素的切割，在体内限制早期中性粒细胞进入炎症部位；(Iii)单核细胞ADAM17在体外促进单核细胞在内皮细胞之间的转运，以及(Iv)巨噬细胞ADAM17促进炎症的消退。我们的总体假设是，ADAM10和ADAM17对关键炎症蛋白的细胞、底物和接触特异性切割对炎症反应的调节至关重要。拟议的研究将建立在这些观察的基础上，通过确定：1)跨膜酶ADAM10和ADAM17调节炎症反应的体外和体内机制；以及2)建立ADAM10和ADAM17的底物，负责调节单核细胞进出炎症部位。这些研究有可能确定生物标记物，以识别患有慢性炎症性疾病的风险患者，并帮助确定他们的治疗策略。

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.