Grant: Project Grant

Sepsis, or the severe inflammation in response to an infection, is one of the leading causes of death of Canadians in the hospital. Sepsis occurs when the immune system is activated by lipid molecules from invading bacteria. These "pathogen-associated lipids", or PALs, are transported through the bloodstream by lipoproteins, the same particles that also transport cholesterol. Of the different lipoprotein particles, HDL (also called the "good cholesterol") plays a particularly important role in transporting PALs. HDL levels are known to drop acutely during sepsis, and we have recently shown that the degree of drop in HDL during sepsis is a very strong predictor of whether or not a patient will survive sepsis, with a lower HDL level predicting a worse outcome. How and why HDL levels drop during sepsis is unknown. The major goal of this project is to investigate genetic mechanisms that determine HDL levels in sepsis. We have discovered a gene, called CETP, that appears to play a very important role in determining HDL levels during sepsis, and thereby contributes to whether or not a patient will survive the episode of sepsis. The goals of this proposal are to explore whether inhibition of CETP may represent a new treatment strategy for sepsis. To do this, we will use an existing drug that inhibits CETP to examine its effects in mouse models of sepsis. We will also investigate the role of genetic variation in HDL-related genes on HDL levels and survival from sepsis in large population cohorts. This research will provide new insight into the important role of HDL and CETP in sepsis. The results of this research could lead to new ways to treat sepsis, for example by altering the function of CETP. Ultimately these results will improve the health of Canadians by leading to new approaches to treat sepsis, one of the leading causes of death in Canada.