Silverstein

Roy L. Silverstein, M.D.

Department Chair

The Jan Bleeksma Chair in Vascular Cell Biology and Atherosclerosis

Professor of Molecular Medicine, Cleveland Clinic Lerner College of Medicine
Staff in Hematologic Malignancies and Blood Disorders, Taussig Cancer Center Department of Cell Biology, Lerner Research Institute
The Cleveland Clinic Foundation
9500 Euclid Avenue NC-10
Cleveland, Ohio 44195
Telephone: (216) 444-5220
Fax: (216) 444-9404
silverr2@ccf.org

Area of general research interest:

Vascular biology, including thrombosis, angiogensis, atherosclerosis, and inflammation

Current program:

  • Role of CD36 in platelet function
  • CD36 signaling in vascular cells
  • Regulation of angiogenesis by TSR containing proteins

Investigators:

  • Wei Li, M.D., Ph.D., Project Scientist
  • S. Ohidar Rahaman, Ph.D., Research Associate
  • Phil Klenotic, Ph.D., Postdoctoral Fellow
  • Mette Johansen, Ph.D., Postdoctoral Fellow
  • David Kennedy, Ph.D., Postdoctoral Fellow
  • Wenxin Huang, Ph.D., Postdoctoral Fellow
  • Young-Mi Park, M.D., Graduate Student (CWRU Program in Cell Biology)
  • Kan Chen, Graduate Student (CWRU Program in Cell Biology)
  • Ling-Yun Chu, Graduate Student (CWRU Program in Cell Biology)
  • Sowmya Srikanthan, Graduate Student (CWRU Molecular Medicine Program)
  • James Hale, Graduate Student (CSU Biology Program)
  • Jennifer Major, Principal Technician
  • Aditya Mandawat, Medical Student (CWRU)

K12 Scholars Affiliated with Lab:

  • Sangeeta Kashyap, M.D., Staff in Endocrinology, Diabetes and Metabolism (CCF)
  • Kurt Lu, M.D., Assistant Professor of Dermatology (Case/UH Medical Center)

Brief Description:

My laboratory is primarily interested in vascular biology, particularly in relationship to the molecular pathogenesis of thrombosis, atherosclerosis, aberrant angiogenesis, inflammation, and thrombosis. We are actively studying cellular phagocytic and adhesion receptors and are interested in how cells regulate expression of these molecules and in the mechanisms by which they transmit cellular transmembrane signals. Much of the focus of the lab is directed to understanding the molecular and cellular biology of a cell surface protein known as CD36. Although this was originally described as an adhesion receptor, we now know that CD36 functions primarily as a scavenger or “pattern recognition” receptor on phagocytic cells, including macrophages, dendritic cells and retinal pigment epithelial cells (RPE). On macrophages CD36 plays a major role in mediating binding and uptake of oxidatively modified low density lipoprotein (LDL). This interaction leads the cells to differentiate into pathological “foam cells” and is critical to the development of atherosclerotic plaque. On dendritic cells CD36 appears to be involved in uptake of apoptotic cells and subsequent antigen presentation, while on RPE it regulates uptake of shed photoreceptor outer segments. We are studying structure-function relationships of CD36, the mechanisms by which CD36 transmits internalization and activation signals, and we have generated a CD36 null mouse to study its role in vivo. The latter studies have pointed to an important role in the pathogenesis of several diseases, including atherosclerosis, malaria, cancer and thrombosis. A significant new project in the laboratory focuses on the mechanisms of CD36 function in blood platelets and the role of CD36 in pathological thrombus formation where we have shown that absence of CD36 can protect against pathological thrombosis.

Another area of research in the laboratory is the regulation of new blood vessel growth and development, a process known as angiogenesis. Although angiogenesis is required for normal embryonic development and postnatal developmental events, such as wound healing, pathological angiogenesis plays an important role in tumor growth, arthritis, retinal degeneration, and obesity. We have found that CD36 on the surface of capillary endothelial cells mediates the anti-angiogenic activity of the matrix glycoprotein thrombospondin. Research in the laboratory is now focused on understanding the nature of the anti-angiogenic intracellular signaling cascade initiated by CD36, the regulation of this signaling system by a protein antagonist, HRGP, and the role of this system in diseases, such as cancer. Numerous approaches are being taken, including study of murine transgenic and knock out animals.

Key References:

Jimenez B., Volpert, O.V., Crawford, S.E., Febbraio, M., Silverstein, R.L., and N.P. Bouck.  2000.  Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1.  Nature Medicine 6:41-48. 

Febbraio, M., Podrez, E.A., Smith, J.D., Hazen, S.L., Hoff, H.F., Sharma, K., Hajjar, D.P., and R.L. Silverstein.  2000.  Targeted disruption of the Class B scavenger receptor, CD36, protects against atherosclerotic lesion development in mice.  J. Clin. Invest. 105:1049-1056.

Simantov, R., Febbraio, M., Crombie, A.R., Asch, A.S., Nachman, R.L., and R.L. Silverstein. 2001.  Histidine Rich Glycoprotein Inhibits the Anti-Angiogenic Effect of Thrombospondin-1.  J. Clin. Inv. 107:45-52.

Febbraio, M., Hajjar, D.P., and R. L. Silverstein.  2001.  CD36: A Class B Scavenger Receptor involved in angiogenesis, atherosclerosis, inflammation and lipid metabolism.  J. Clin. Inv. 108: 785-791.

Finnemann, S.C. and R. L. Silverstein. 2001.  Differential roles of CD36 and αvβ5 integrin in photoreceptor phagocytosis by the retinal pigment epithelium. J. Exp. Med. 194:1289-98. 

Podrez, E.A., Batyreva, E. Shen, Z., Zang, R., Deng, Y., Sun, M., Finton, P.J., Shen, L., Febbraio, M., Hajjar, D.P. Silverstein, R.L., Hoff, H.F., Salomon, R.G., and S.L. Hazen.  2002.    A novel family of atherogenic oxidized phospholipids promotes macrophage foam cell formation via the scavenger receptor CD36 and is enriched in atherosclerotic lesions.  J. Biol. Chem. 277:38517-38523.

Simantov, R., Febbraio, M. and R.L. Silverstein. 2005. The anti-angiogenic effect of thrombospondin-2 is mediated by CD36 and inhibited by Histidine-rich Glycoprotein.  Matrix Biology 24:27-34

Ahn, J.C., Febbraio, M.,  and R. L. Silverstein. 2005. A novel isoform of human Golgi-localized Glycoprotein-1 (also known as E-selectin ligand-1, MG-160, and cysteine-rich fibroblast growth factor receptor) targets differential subcellular localization.  J. Cell Science 118:1725-31.

Cho, S., Park, E-M., Febbraio, M., Anrather, J., Park L., Racchumi, G., Silverstein, R.L., and Iadecola, C.  2005.  The Class B Scavenger Receptor CD36 Mediates Free Radical Production and Tissue Injury in Cerebral Ischemia.  J. Neuroscience 25:2504-2512.

Sun, M., Finnemann, S.C., Febbraio, M., Shan, L., Annangudi, S.P., Podrez, E.A., Hoppe, G., Darrow, R., Organisciak, D.T., Salomon, R.G., Silverstein, R.L., and Hazen, S.L. 2006. Light-induced oxidation of photoreceptor outer segment phospholipids generates ligands for CD36-mediated phagocytosis by retinal pigment epithelium: A potential mechanism for modulating outer segment phagocytosis under oxidant stress condition. J. Biol. Chem. 281(7):4222-30.

Rahaman, S.O., Lennon, D.J., Febbraio, M., Podrez, E.A., Hazen, S.L., and R. L. Silverstein. 2006. CD36-dependent activation of c-Jun N-terminal kinase by oxidized LDL is required for macrophage foam cell formation.  Cell Metabolism 4(3):211-221.

Goodman, O.B., Jr, Febbraio, M., Simantov, R., Zheng, R., Shen, R., Silverstein, R.L. and D.M. Nanus. 2006.  Neprilysin inhibits angiogenesis via proteolysis of fibroblast growth factor-2. J. Biol. Chem. 281(44):33597-605.

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

Guy, E., Kuchibhotla, S., Silverstein, R.L. and M Febbraio. 2007. Continued Inhibition of Atherosclerotic Lesion Development in Long Term Western Diet Fed CD36o/apoEo Mice. Atherosclerosis. 192(1):123-30.

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.  2007.  Hazen. 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 R.L. Silverstein.  2008. Platelet CD36 mediates interactions with endothelial cell-derived microparticles and contributes to thrombosis in vivo.  J. Clin. Inv. (in press).

Chen, K., Li, W., Febbraio, M, and R. L. Silverstein.  A specific CD36-dependent signaling pathway is required for platelet activation by oxidized LDL.  (in press)

Ghosh, A., Zhang, L., Chen, K., Murugesan, G., Hu, Y., Wang, Q., Febbraio, M., Barnard, J., and R.L. Silverstein. CD36 surface expression level on platelets affects functional responses to oxidized LDL and is associated with inheritance of specific genetic polymorphisms.  (submitted)

Klenotic, P., Febbraio, M., Van Meir, E.G., and R. L. Silverstein.  2008.  Histidine-rich Glycoprotein Modulates the Anti-angiogenic Effects of Vasculostatin. (submitted)

Park, Y.M., Febbraio, M. and R. L. Silverstein.   2008.  CD36 modulates macrophage migration in response to oxidized LDL: A mechanism of macrophage trapping.  (submitted)