Characterization and function of a novel receptor in smooth muscle cells

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Proteins called receptors are on the surfaces of cells. Chemical compounds bind to receptors and cause cell responses that regulate the normal function of tissues and organs. Receptors are diverse and their importance varies according to the type of cell. For example, in blood vessels the smooth muscle cells regulated blood flow, an important role in oxygen and nutrient delivery to organs. In blood vessel the receptors on smooth muscle can cause them to shorten or contract, which increases the resistance to blood flow. More than 80% of pharmaceutical drugs target receptors like those present on the surface of smooth muscle cells. For many receptors, the identity of the chemicals (ligands) that activate the receptor are unknown. We call these latter type orphan receptors. Identifying the ligands for orphan receptors is one strategy being used by the pharmaceutical industry to develop new drug entities. Therefore, identifying the ligands for an orphan receptor can be a significant scientific discovery that can have long-term impact on the research community and society. The goal of our NSERC research is to study a novel receptor by looking at how it causes blood vessel contraction and thereby changes blood flow in whole organisms. We will also use this information to see whether the receptor is found elsewhere and to determine its function in those other tissues and systems. In previously published work, we identified a novel receptor that has a role in vascular smooth muscle cell function. This receptor causes blood vessel constriction, which would be anticipated to increase blood pressure and decrease blood flow to organs. What is particularly novel about this program is that the identity of the receptor and the scope of biological activities associated with the ligand (test-compound) have not been determined. We will conduct lab experiments to identify the receptor and describe the biochemical mechanisms that cause smooth muscles to contract by using cells isolated from blood vessels of mice. To show that our results have meaning for the whole organism (the physiological importance), we will conduct testing in live animals to study a compound that activates the contraction mechanism. Additional experiments will be used to further characterize the activity and function of this receptor in vascular tissues first; later in other tissues. This program will support the training of highly-qualified PhD scientists that will be highly likely to make original discoveries with broad scientific impact. These people will have skills to make them highly adaptable to different future research environments either in academia or industry research and will have experience with leading research teams. This program will establish laboratory basic science evidence about a cell receptor that may lead to creation of new materials for future technology transfer and commercialization.