CD73 & THROMBOMODULIN

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 CD 73是一种糖基磷脂酰肌醇（GPI）连接的膜蛋白，催化AMP的细胞外去磷酸化为腺苷。血栓调节蛋白（TM）是位于内皮细胞表面的I型跨膜蛋白。它作为凝血酶调节剂，因为凝血酶的底物特异性一旦与TM结合就被转换。在这项研究中，我们提出，CD 73产生的腺苷调节TM的表达和TM是一个目标的CD 73产生的腺苷信号通路。具体目标是：1.探讨CD 73调控内皮细胞TM表达的途径及其对TM功能的影响。2.目的研究CD 73在TM调节中的作用及对TM功能的影响。3.目的：探讨抗凝系统在CD 73功能中的作用。 我们的初步结果表明，TM表达水平上调腺苷受体激动剂在体外和体内。CD 73产生的腺苷也可以在体外增加TM表达。在这个提议中，我们将确定负责TM调节的腺苷受体亚型和下游效应子。对TM功能的影响将通过蛋白C对内皮细胞的激活来表征。我们比较了正常条件下CD 73-/-小鼠与野生型小鼠的TM表达水平。这些比较将在炎症条件下进行。通过测量炎症条件下野生型小鼠和CD 73-/-小鼠血浆中的APC水平来表征对TM功能的影响。还将在几个实验设置下研究抗凝系统对CD 73功能的影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. CD73 is a glycosylphosphatidylinositol (GPI)-linked membrane protein that catalyzes the extracellular dephosphorylation of AMP to adenosine. Thrombomodulin (TM) is a type I transmembrane protein located on the surface of endothelial cells. It serves as a thrombin modulator, since thrombin's substrate specificity is switched once binding to TM. In this study, we proposed that CD73-generated adenosine regulates TM expression and TM is a target of the CD73-generated adenosine signaling pathway. The specific aims are: 1. To delineate the pathway of CD73 regulated TM expression and the impact on TM functions in cultured endothelial cells. 2. To study the role of CD73 on TM regulation and the impact on TM functions in mouse model. 3. To study the role of anti-coagulation system involved in CD73 functions. Our preliminary results indicated that TM expression levels were up-regulated by an adenosine receptor agonist in vitro and in vivo. CD73-generated adenosine also can increase TM expression in vitro. In this proposal, we will identify the adenosine receptor subtype responsible for TM regulation and the downstream effectors. The impact on TM functions will be characterized by protein C activation on endothelial cells. We have compared TM expression levels in CD73-/- mice to that in wild type mice under normal conditions. These comparisons will be carried out under inflammatory conditions. The impact on TM functions will be characterized by measuring APC level in plasma in wild type mice and CD73-/- mice under inflammatory conditions. The impact of anti-coagulation system on CD73 functions will also be studied under several experimental settings.