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Jonathan D. Smith, Ph.D.

Staff

Department of Cell Biology
Lerner Research Institute / NC10
9500 Euclid Avenue
Cleveland, Ohio 44195
Telephone: (216) 444-2248
Fax: (216) 444-9404
smithj4@ccf.org

Areas of general research interest:

The pathobiology and genetics of atherosclerosis and atrial fibrillation, and the mechanisms involved in reverse cholesterol transport.

Current research programs:

  • Identification of genes that modify atherosclerosis susceptibility in mice and humans
  • Use of expression microarrays and bioinformatics to aid in the discovery of genes for complex traits
  • Identification of genes that modify susceptibility to atrial fibrillation in humans though candidate gene and genome wide association studies.
  • Characterization of the mechanism of cholesterol and lipid efflux via ABCA1 and the effects of inflammation on reverse cholesterol transport
  • Discovery of novel ApoAI variants with altered structure, function, and resistance to oxidative damage
  • Characterization of a novel pathway for the uptake of lipoprotein cholesterol in macrophages
  • Identification of novel compounds that my be useful for the prevention of Alzheimer disease

Education and professional positions held:

  • 2004-present: Professor, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University
  • 2002-present: Full Staff, Department of Cell Biology, Lerner Research Institute, The Cleveland Clinic, Cleveland , OH , Adjunct in Department of Cardiovascular Medicine
  • 2006-present: CCF Professor in the Department of Biological, Geological, and Environmental Sciences, Cleveland State University.
  • 2005-present: CCF Professor in the Department of Chemistry, Cleveland State University
  • 1997-2002: Associate Professor, Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University , New York , NY
  • 1989-1996: Assistant Professor, Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University , New York , NY
  • 1984-1989: Postdoctoral fellow, Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, New York, NY
  • 1978-1984: Graduate student in Cellular and Developmental Biology at Harvard University Division of Medical Sciences, Ph.D. awarded 6/84
  • 1973-1978: Undergraduate studies and research in biology at University of California at Santa Cruz , B.A. awarded 3/78

Research Description

Atherosclerosis, the most common cause of cardiovascular disease and stroke, is initiated when monocytes enter the arterial wall and differentiate into macrophages, which take up lipoproteins to become lipid-engorged foam cells. We study two aspects of atherosclerosis:

(1) The mechanisms by which macrophages can get rid of excess cholesterol in a protective process known as reverse cholesterol transport. This involves moving cholesterol out of the cell via a protein called ABCA1 and assembling this cholesterol onto apolipoproteins to form high-density lipoprotein. We are investigating how ABCA1 transfers lipids from the cell to apoAI. We are also studying how apoAI can be inactivated by an oxidative mechanism, which makes apoAI unable to participate in reverse cholesterol transport.

(2) The genes that alter atherosclerosis susceptibility in a mouse model. We have bred apoE-deficient mice, which have high levels of plasma cholesterol and develop atherosclerosis spontaneously, onto different inbred mouse strains and found strains with large differences in lesion areas.

We are using mouse genetic methods to map and identify genes that cause the large strain effects on atherosclerosis. We are also performing expression microarray studies to define which genes have expression differences that correlate with lesion susceptibility.

We hope that identifying these mouse atherosclerosis susceptibility genes will lead to insights into the pathogenesis of human atherosclerosis.

Selected Recent Publications

  1. Bhasin, J.M., Chakrabarti, E., Peng, D.Q. Kulkarni, A., Chen, X., and Smith, J.D. Sex Specific Gene Regulation and Expression QTLs in Mouse Macrophages from a Strain Intercross. (2008) PLOS One 3: e1435.
  2. Wu. Z., Wagner, M.A., Zheng, L., Parks, J.S., Shy, J.M., Smith, J.D., Gogonea, V., and Hazen, H.L.  The refined structure of nascent HDL reveals a key functional domain for particle maturation and dysfunction. (2007) Nature Struct Biol 14: 861-868.
  3. Zhu, K., Brubaker, G., Smith, J.D.  Large disc intermediate precedes formation of apolipoprotein A-I DMPC small discs. (2007) Biochemistry 46: 6299-6307.
  4. Smith, J.D., Bhasin, J.M., Baglione, J., Settle, M., Xu, Y., and Barnard, J. Atherosclerosis susceptibility loci identified from a strain intercross of apoE-deficient mice via a high density genome scan. (2006) Arterioscl Thromb Vasc Biol 26: 597-603.
  5. Smith, J.D., Peng, D.-Q., Dansky, H.M., Settle, M., Baglione, J., Le Goff, W., Chakrabarti, E., Xu, Y., and Peng, X. Transcriptome profile of macrophages from atherosclerosis sensitive and resistant mice. (2006) Mamm Genome 17: 220-229..
  6. Le Goff, W., Zheng, P., Brubaker, G., and Smith, J.D. Identification of the cAMP responsive enhancer of the murine ABCA1 gene: Requirement for CREB1 and STAT3/4 elements. (2006) Arterioscl Thromb Vasc Biol 26: 527-533.
  7. Brubaker G., Peng, D-Q., Somerlot, B., Abdollahian, D., and Smith, J.D. Effects Apolipoprotein A-I lysine modification: Effects on helical content, lipid binding, and cholesterol acceptor activity. (2006) Biochim Biophys ACTA 1761: 64-72
  8. Le Goff, W., Settle, M., Greene, D.J., Morton, R.E., and Smith, J.D. Reevaluation of the role of the multidrug resistant P-glycoprotein in cellular cholesterol homeostasis. (2006) J Lipid Res 47: 51-58.
  9. Peng, D.-Q., Wu, Z., Brubaker, G., Zheng, L., Settle, M., Gross, E., Kinter, M., Hazen, S.L., and Smith, J.D. Tyrosine modification is not required for myeloperoxidase-induced loss of apolipoprotein A-I functional activities. (2005) J Biol Chem 280: 33775-33784.
  10. Chakrabarti, E. and Smith, J.D. Drug library screen to identify compounds that decrease secreted Ab from a human cell line. (2005) Curr Alz Res 2 : 255-259.
  11. Zheng, L.,Settle, M., Brubaker, G., Schmitt, D., Hazen, S.L., Smith, J.D. and Kinter, M. Localization of nitration and chlorination sites on apolipoprotein A-I catalyzed by myeloperoxidase in human atheroma and associated oxidative impairment in ABCA1-dependent cholesterol efflux from macrophages. (2005) J Biol Chem 280: 38-47.
  12. Le Goff, W., Peng, D.-Q., Settle, M., Brubaker, G., Morton, R.E., and Smith, J.D. Cyclosporin A traps ABCA1 at the plasma membrane and inhibits ABCA1-mediated lipid efflux to apolipoprotein A-I. (2004) Arterioscl Thromb Vasc Biol 24: 2155-2161.
  13. Zheng, L., Nakuna, B., Brennan, M.-L., Sun, M., Goormastic, M., Settle, M., Schmitt, D., Fu, X., Thomson, L., Fox, P.L., Ischiropoulos, H., Smith, J.D. , Kinter, M., and Hazen S.L. Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease. (2004) J Clin Invest 114: 529-41.
  14. Smith, J.D. , Le Goff, W., Settle, M., Brubaker, G., and Oda, M, N. ABCA1 mediates concurrent cholesterol and phospholipid efflux to apoAI. (2004) J Lipid Res 45: 635-644.
  15. Zheng, P., Pennacchio, L.A. , Le Goff, W., Rubin, E.M., and Smith, J.D. Identification of a novel enhancer of brain expression near the apoE gene cluster by comparative genomics. (2004) Biochim Biophys ACTA 1676: 41-50.