Roy Siverstein, MD Portrait

Roy L. Silverstein, MD

 
Senior Investigator
Blood Research Institute
BloodCenter of Wisconsin
 
John and Linda Mellowes Professor and Chairman
Department of Medicine
Medical College of Wisconsin
 
Education and training
MD, Emory University School of Medicine, 1979
Residency in Internal Medicine, Hematology and Medical Oncology, New York Hospital Cornell Medical Center
 
Contact information
Phone: (414) 805-0518
Fax: (414) 805-0524

Thrombosis, Hemostasis and Vascular Biology
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.

Grants
  • NIH/NHLBI – R01HL085718, Regulation of angiogenesis by CD36/TSP/HRGP (2008-2013)
  • NIH/NHLBI – R01HL111614, Mechanistic role of CD36 in thrombosis (2013-2017)


Bin Ren, MD, PhD

Research Scientist I
Assistant Professor of Medicine, Medical College of Wisconsin

Yiliang Chen, PhD
Postdoctoral Fellow

Gabriella Kartz, PhD
Postdoctoral Fellow

Wenxin Huang, PhD
Sr Research Associate

Deviprasadh Ramakrishdeviprasadh
Graduate Student

Moua Yang
Graduate Student

Rong Yuan
Research Lab Technician

Publications
Representative and Recent Publications:
  • Febbraio, M., Podrez, E.A., Smith, J.D., Hazen, S.L., Hoff, H.F., Sharma, K., Hajjar, D.P., and Silverstein R.L. 2000. Targeted disruption of the Class B scavenger receptor, CD36, protects against atherosclerotic lesion development in mice. J. Clin. Invest. 105:1049-1056.
  • Finnemann, S.C. and Silverstein R.L. 2001. Differential roles of CD36 and αvβ5 integrin in photoreceptor phagocytosis by the retinal pigment epithelium. J. Exp. Med. 194:1289-1298.
  • Greenberg, M.E., Sun, M., Zhang, R., Febbraio, M., Silverstein, R.L., and S.L. Hazen. 2006. Oxidized phosphatidylserine-CD36 interactions play an essential role in macrophage dependent phagocytosis of apoptotic cells. J. Exp Med. 203(12): 2613-25
  • Podrez, E.A., Byzova, T.V., Febbraio, M., Salomon, R.G., Ma, Y., Valiyaveettil, M., Poliakov, E., Sun, M., Finton, P.J., Curtis, B.R., Chen, J., Zhang, R., Silverstein, R.L., and S.L. Hazen. 2007. Platelet CD36 links hyperlipidemia, oxidant stress and a pro-thrombotic phenotype. Nature Medicine 13(9):1086-1095.
  • Ghosh, A., Li, W., Febbraio, M., Espinola, R.G., McCrae, K., and Silverstein R.L. 2008. Platelet CD36 mediates interactions with endothelial cell-derived microparticles and contributes to thrombosis in vivo. J. Clinical Investigation 118 (5):1934-1943.
  • Chen, K., Febbraio, M., Li, W., and Silverstein R.L. 2008. A specific CD36-dependent signaling pathway is required for platelet activation by oxidized LDL. Circulation Research 102;1512-1519.
  • Kaur, B., Sandberg, E.M., Devi, N.S., Zhang, S., Shim, H., Mao, H., Febbraio, M., Klenotic, P., Cork, S., Silverstein, R.L., Crat, D.J., Olson, J.J., and E.G. Van Meir. 2009. Vasculostatin inhibits intracranial glioma growth and negatively regulates in vivo angiogenesis through a CD36-dependent mechanism. Cancer Research; 69:1212-1220.
  • Park, Y.M., Febbraio, M. and Silverstein R.L.   2009. CD36 modulates migration of mouse and human macrophages in response to oxidized LDL and contributes to macrophage trapping in the arterial intima. J. Clin. Invest. 119(1):136-145.
  • Kashyap, S.R., Ioachimescu, A., Gornik, H.L., Gopan, T., Davidson, M., Makdissi, A., Major, J., Febbraio, M., and Silverstein R.L. 2009. Lipid induced insulin resistance is associated with increased monocyte expression of scavenger receptor CD36 and internalization of oxidized LDL. Obesity. 17(12):2142-8.
  • Klenotic, P., Febbraio, M., Van Meir, E.G., and Silverstein R.L. 2010. Histidine-rich glycoprotein modulates the anti-angiogenic effects of vasculostatin. Am. J. Path;176(4):2039-50.
  • Lvovich V.F., Srikanthan S., Silverstein R.L. 2010. A novel broadband impedance method for detection of cell-derived microparticles. Biosens. Bioelectr. 26:444-451.
  • Kennedy, D.J., Kuchibhotla, S., Silverstein, R.L., Morton, R.E., and M. Febbraio. (2010). CD36 Mediates a Pro-inflammatory Signaling Loop in Fat and Contributes to Insulin Resistance Cardiovascular Research. Dec. 16 (epub ahead of print).
  • Li, W., Febbraio, M., Reddy, S.P., Yu, D.-Y., Yamamoto, M., and Silverstein R.L. 2010. CD36 participates in a signaling pathway that regulates reactive oxygen species formation by vascular smooth muscle cells. J. Clin. Invest. 120(11):3996-4006.
  • Rahaman, S.O., Febbraio, M., Zhou, G., Swat, W., and Silverstein R.L. 2011. Vav proteins mediate a CD36-dependent pro-atherogenic macrophage phenotype. J. Biol. Chem; 286(9):7010-7017.
  • Ren, B., Hale, J., Srikanthan, S., and Silverstein R.L. 2011. Lysophosphatidic Acid Suppresses Endothelial Cell CD36 Expression and Promotes Angiogenesis via a PKD- 1 Dependent Signaling Pathway. Blood. 117(22):6036-45.
  • Chen, K., Li, W., Major, J., Febbraio, M., and Silverstein R.L. 2011. Vav guanine nucleotide exchange factors link hyperlipidemia and a prothrombotic state.  Blood. 117(21):5744-50
  • Ghosh, A., Murugesan, G., Chen, K., Zhang, L., Wang, Q., Febbraio, M., Anselmo, R.M., Marchant, K., Barnard, J., and Silverstein R.L. 2011. Platelet CD36 surface expression levels affect functional responses to oxidized LDL and are associated with inheritance of specific genetic polymorphisms. Blood 117(23):6355-66.
  • Klenotic, P.A., Page, R.C., Misra, S., and Silverstein R.L. 2011. Expression, purification and structural characterization of functionally replete Thrombospondin-1 type 1 repeats in a bacterial expression system. Protein Expression and Purification 80(2):253-9
  • Rahaman, S. O., Zhou G., and Silverstein R.L. 2011. Vav GEF regulates CD36-mediated macrophage foam cell formation via calcium and dynamin-dependent processes. J. Biol. Chem. 286(41):36011-9
  • Huang, W., Febbraio, M., and Silverstein R.L. 2011. Macrophage CD9 co-localizes with CD36 and participates in CD36-dependent responses to oxidized low density lipoprotein. PLos One 6(12):e29092. Epub 2011 Dec 21.
  • Chu, L.-Y. and Silverstein R.L. 2012. CD36 ecto-domain phosphorylation blocks thrombospondin-1 binding: structure - function relationships and regulation by protein kinase C. Arteriosclerosis, Thrombosis and Vascular Biology. Jan 12. [Epub ahead of print]
  • Park, Y.M., Kashyap, S., Major, J., and Silverstein R.L. 2012. Insulin promotes macrophage foam cell formation: Potential implications in diabetes-related atherosclerosis. Lab. Invest. (in press).
  • Zhu,W., Li, W., and Silverstein, R.L. 2012. Advanced glycation end products induce a pro-thrombotic phenotype in mice via interaction with platelet CD36. Blood (in press)
  • Park, Y.M., Drazba, J.A., Egelhoff, T., Vasanji, A., Febbraio, M., and Silverstein R.L. 2012. Oxidized LDL/CD36 interaction induces loss of cell polarity and inhibits macrophage locomotion. Molecular Biology of the Cell (under revision)
  • Silverstein, R.L. and M. Febbraio. 2009. CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior. Science Signaling 2, re3.
  • Silverstein, R.L. 2012. Teaching an old dog new tricks: potential anti–athero-thrombotic use for statins. J. Clin. Invest. 122(2):478-81

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