Grant: Project Grant

Our bodies have systems in the blood that co-ordinately respond to injuries: the blood clotting system controls bleeding, and the immune system removes damaged cells and infection. If these systems are out of balance due to genetic or environmental factors, bleeding may persist or too much clotting may occur; infections may spread or too much inflammation may cause organ damage. Such imbalances are manifest as disease (e.g. heart disease, stroke, venous thrombosis, atherosclerosis, haemophilia). A major trigger of these systems is a protein called Tissue Factor (TF). TF is made by cells wrapped around blood vessels. With an injury, TF is exposed to the blood and initiates clot formation and turns on the immune system. TF has partner proteins that assemble and function in complex ways that are incompletely understood, yet important to understand. Indeed, such information will help in designing treatments to correct imbalances that may cause disease. We recently uncovered a protein, CD248, that interacts with TF and increases its clotting activity. Mice that lack CD248 are resistant to the formation of excess blood clots. The mice are also protected against inflammatory disease. Our findings are important, as they may point to the development of drugs that reduce CD248 to treat or prevent several diseases. This proposal aims to better understand how CD248 works. We will figure out which CD248-producing cells are important by using mice that do or do not have CD248 in different cells. The mice will be challenged by inducing blood clots and inflammation to replicate what happens in humans. We expect that reducing CD248 in one or the other cell, will be protective. In other experiments, we will figure out how CD248 participates with TF and its partners in controlling blood clotting and inflammation. We hope our results will yield new information for the design of better therapies for patients who otherwise suffer from immune and/or clotting & bleeding disorders.