Transcriptional and Translational Regulation of the Ectoenzyme CD39 and its Role in In Vivo Thromboregulation.

Abstract

Extracellular purinergic signaling through ATP and ADP has been shown to be a potent trigger for inflammation and thrombosis. Modulating the purinergic signaling pathway is the plasmalemmal ectonucleotidase, CD39/NTPDase1 (ectonucleoside triphosphate diphosphohydrolase). CD39 is expressed by a number of cell types including endothelial cells, B and T lymphocytes, and monocytes and macrophages. It hydrolyzes the terminal phosphate of ATP and ADP in an enzymatic cascade that generates AMP.

Under pathological conditions such as atherosclerosis, deep vein thrombosis and ischemia of various organs, the coexisting pathways of inflammation and thrombosis contribute to disease progression. As such, those enzymes and key steps in the various signaling pathways involved in inflammation and those involved in coagulation are targets for future therapies. CD39 is one such enzyme, which can modulate purinergic signaling pathways to limit thrombosis and inflammation. Interest in CD39 and its function has grown since its discovery, and much has been learned about its protective role against thrombosis, its sequence and structure, its activity under targeted mutations, and its role in inflammatory and thrombotic disease models. There remain, however, many gaps in our basic knowledge about CD39. To address these gaps and to contribute in a meaningful way to the body of work surrounding CD39, three projects were designed, focused on regulation of CD39 on both the transcriptional and translational levels as well as its in vivo actions. The work presented here investigates the possibility of pharmacologically regulating expression and activity as well as the microenvironment in which it resides. Furthermore, these experiments address the issue of how this regulation might modulate the capacity of CD39 to function, and the protective effects of this in an integrated biological system.