Our laboratory studies basic pathophysiologic mechanism underlying common vascular diseases, especially thrombosis, atherosclerosis and neoplastic angiogenesis. 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 three major projects funded by NIH.
As a receptor for TSR proteins, CD36 functions on microvascular endothelial cells as an important anti-angiogenic receptor and negative regulator of angiogenesis. One of the major projects in the lab is centered on understanding the endothelial cell signaling pathway triggered by TSR-CD36 interactions and, more importantly to understand mechanisms by which tumor endothelium becomes resistant to TSR-mediated anti-angiogenesis. This project includes studies on epigenetic down-regulation of CD36 expression triggered by the lipid signaling molecule LPA, characterization of an endogenous soluble “decoy” receptor for TSR, known as histidine-rich glycoprotein, characterization of the structural basis of TSR-CD36 binding, and dissecting the CD36 signaling pathway in endothelial cells. The ultimate goal is to develop therapeutic approaches to enhance or inhibit angiogenesis by targeting this pathway.
The second 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, and a guanine nucleotide exchange factor known as Vav, and results in enhanced platelet reactivity. Studies of mouse models and human populations have linked this pathway to important pro-thrombotic states, including diabetes, atherosclerosis and inflammation.
The third major 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 also promotes oxidant stress in the blood vessel wall. We hope that we can target this pathway to promote atherosclerotic plaque resolution. Other studies focus on identifying cell membrane proteins that cooperate with CD36 in cell signaling, including tetraspanins, toll-like receptors, and the sodium-potassium APTase and understanding the structural basis of CD36 interactions with these partner proteins.
Bin Ren, MD, PhD
Research Scientist I
Assistant Professor of Medicine, Medical College of Wisconsin
Yiliang Chen, PhD
Gabriella Kartz, PhD
Wenxin Huang, PhD
Sr Research Associate
Research Lab Technician
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