Project 461655

A healthy circulation is essential to good health and depends on the functioning of blood vessels, especially the endothelial cells lining the inside of the vessels. Preventive therapies such as diet and lifestyle modification and drug treatments for high blood pressure, clogged arteries, diabetes, metabolic syndrome, and stroke are indirectly effective because they improve, protect, or mimic the healthy functions of endothelial cells. However, no prescribed drugs directly target endothelial cell functions. We need new therapeutic options to replace drugs that are ineffective for chronic treatment or are avoided by patients due to adverse effects. Restoring endothelial function will even improve some treatments. Our goal is to examine the endothelial cells and study a receptor called PAR2. We want to understand how this receptor works in normal healthy endothelial cells and how to use its novel mechanisms as drug therapies in human diseases. We also want to know what problems may arise if PAR2 is targeted for diseases. In this study, we will use animals (mice) and cells isolated from humans. We will study the ways by which PAR2 drugs work in experiments using cells, and blood vessels. We will create a chemical library of novel PAR2 compounds. We have created a unique mouse strain where the endothelium does not have any PAR2. We will screen the library to identify promising PAR2 agents and look to see if blood pressure and blood vessel functions are changed by removing PAR2 only in endothelial cells. PAR2 causes blood vessel dilation, which lowers blood pressure in lab models and increases blood flow in healthy human volunteers, two effects that may be useful in treatment of disease. There are many functions of PAR2 and the endothelium. We aim to understand how PAR2 controls these effects to see there is way to be selective with PAR2. We will provide basic science lab evidence and new tools which may be used to develop therapeutics targeting PAR2 in human disease.