Grant: Operating Grant

When a person sustains an injury, the major risks to their well-being are excess bleeding and overwhelming infection and inflammation (swelling, redness, pain). Fortunately, we have systems in our blood that reduce the bleeding through the formation of blood clots and prevent the spread of infection and inflammation ("complement system"). These systems cooperate to maintain normal functioning of our organs (e.g. the kidneys, heart, liver, lung and joints) and to promote healing. Alterations in the control of the coagulation and/or complement systems predispose patients to bleed excessively (e.g. in hemophilia), to clot too much (e.g. in deep vein thrombosis or heart attacks), to succumb to mild infections, or to develop inflammatory diseases such as atherosclerosis (inflamed and damaged blood vessels), arthritis (inflamed joints), colitis (inflamed bowels) or nephritis (inflamed kidneys). Unfortunately, these disorders are common and inadequately treated due to an incomplete understanding of how the coagulation and complement systems are controlled. To overcome this, we are focusing our research on "polyphosphate" which is a long string of the metal ion, phosphate. Polyphosphate is released into the blood when injury or infection occurs. Recent studies in our lab show that polyphosphate controls the complement system. Our new and intriguing findings hold promise for the design of novel polyphosphate-based strategies to treat many of the diseases mentioned above. Using biochemical and molecular biologic techniques and genetic mouse models of human disease, we will study the complement pathways in the blood to determine which steps are controlled by polyphosphate and how it works. The information gained will provide us with insights to develop new therapies that modulate the effects of polyphosphate on complement, with hopes of improving the health of many patients.