Thrombosis, Hemostasis and Vascular Biology
Our laboratory studies basic pathophysiologic mechanism underlying common vascular diseases, especially thrombosis and atherosclerosis. The work focuses on a specific cellular receptor known as CD36. This is the defining member of the Type 2 scavenger receptor family and is expressed on the surface of platelets, monocytes, macrophages, capillary endothelial cells, adipocytes and myocytes. CD36 is a multifunctional receptor that recognizes three major classes of ligand: proteins containing the so-called thrombospondin structural homology domain (TSR), free fatty acids, and oxidized phospholipids that are presented by exogenous pathogens and endogenous “danger signals”. Our lab has developed a “tool kit” to study this protein in vivo and in vitro, including genetic knockout mice crossed into several disease model backgrounds, specific antibodies and shRNA reagents, and highly specific ligands. We are currently working on two major projects funded by NIH, American Heart Association, and Advancing a Healthier Wisconsin.
A major project in the laboratory focuses on the role of CD36 on platelets. Our lab discovered that platelet CD36 serves to recognize endogenous “danger signals” generated during inflammation, oxidant stress, diabetes, and cancer. These signals include oxidized LDL (oxLDL), advanced glycated proteins, and cell-derived microparticles. Interaction of these molecules with CD36 initiates a complex signaling pathway involving Src-family kinases, MAP kinases, a guanine nucleotide exchange factor known as Vav, resulting in intracellular generation of reactive oxygen species (ROS) which then results and enhanced platelet reactivity and thrombosis. Studies of mouse models and human populations have linked this pathway to important pro-thrombotic states, including diabetes, atherosclerosis and inflammation. We are using chemical biology techniques to explore downstream protein modifications induced in platelets by CD36-generated ROS with the goal of identifying novel therapeutic and diagnostic targets.
The second project in the lab focuses on the role of CD36 in promoting atherosclerosis, the disease responsible for heart attack and stroke. We have shown in mouse models and cell models that CD36 binds to oxidized LDL (so-called bad cholesterol) and promotes cholesterol accumulation in macrophages and atherosclerotic plaque formation. Current studies focus on understanding the cellular mechanisms of CD36’s pro-atherogenic function. We have discovered a novel signaling pathway that dramatically alters macrophage migration and promotes oxidant stress in the blood vessel wall and linked this to changes in intracellular metabolism and macrophage polarization. We hope that we can target this pathway to promote atherosclerotic plaque resolution.
