Jonathan Smith, PhD
Staff
Geoffrey Gund Endowed Chair for Cardiovascular Research
Email: [email protected]
Location: Cleveland Clinic Main Campus
Research
We apply cell/molecular biology, biochemistry, and genetics/genomics to study three areas related to cardiovascular disease.
- Atherosclerosis is the most common cause of cardiovascular disease and stroke. Atherosclerosis is initiated by high plasma cholesterol leading to monocyte entry into the artery wall and differentiation into macrophages, which take up lipoprotein cholesterol to become lipid engorged foam cells. We are identifying genes that alter atherosclerosis susceptibility in a mouse model and testing whether they play a role in coronary artery disease in humans.
- The mechanism by which macrophages get rid of excess cholesterol is via a protective process known as reverse cholesterol transport. This involves moving cholesterol out of the cell via a membrane protein called ABCA1 and assembling this cholesterol onto apoAI to form HDL. We are studying how ABCA1 transfers lipids from the cell to apoAI. We are also studying how apoAI can become dysfunctional so that it can no longer participate in reverse cholesterol transport. We have created an apoAI variant that is resistant to becoming dysfunctional, which may be useful as a human therapeutic.
- We are also examining the genetics and functional genomics of atrial fibrillation, a common arrhythmia that often leads to strokes. Together with Drs. Mina Chung, Dave Van Wagoner, and John Barnard, we have performed a genome wide association study for atrial fibrillation, and we are now working to determine how these common genetic variants act to alter susceptibility to this disease.
Lay Summary
We apply modern technologies including next generation sequencing to help discover mechanisms and pathways relevant to human cardiovascular disease, such as atherosclerosis, atrial fibrillation, and HDL metabolism. We hope to translate this information into new diagnostic and therapeutic regimens. We are currently performing pre-clinical evaluation of a novel oxidant resistant apoAI isoform that we created.
Biography
Jonathan Smith, PhD, is Professor and Chair of the Molecular Medicine Department of the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. He is also the director of the Molecular Medicine PhD training program. At the Cleveland Clinic Lerner Research Institute, Dr. Smith is Staff in the Department of Cardiovascular & Metabolic Sciences, where he holds the Geoffrey Gund Endowed Chair for Cardiovascular Research. Dr. Smith received his Bachelor degree in Biology at the University of California, Santa Cruz, and his PhD degree in Cellular and Developmental Biology at Harvard University, Division of Medical Sciences. He performed postdoctoral research at Rockefeller University in the laboratory of Jan Breslow, studying apolipoprotein gene expression, lipoprotein metabolism, and mouse models of atherosclerosis. Dr. Smith rose up the ranks to Assistant and Associate Professor at Rockefeller, and joined the Lerner Research Institute in 2002. He has received career awards and career recognition awards from the NIH and the American Heart Association, as well as Excellence in Education awards from the Lerner Research Institute. He has published close to 200 peer reviewed original research papers, and additional reviews and editorials. Dr. Smith’s research is currently funded by two NIH R01 grants, one program project grant led by Dr. Mina Chung, and one strategically focused research grant from the American Heart Association. He is also the principal investigator for the T32 training grant supporting six Molecular Medicine PhD students per year. Dr. Smith has trained numerous PhD students, postdoctoral fellows, medical students, laboratory technicians, as well as high school and college students. He supports enabling underrepresented minority students to enter STEM careers.
Education & Professional Highlights
Education:
1978 University of California, Santa Cruz, B.A. in Biology
1984 Harvard University, Ph.D. in Cellular and Developmental Biology, Division of Medical Sciences
Postdoctoral Training:
1984-1989 Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, New York, NY
Academic Appointments:
1989-1996 Assistant Professor, The Rockefeller University, New York, NY
1997-2002 Associate Professor, The Rockefeller University, New York, NY
2002 - Staff, Department of Cellular & Molecular Medicine, Lerner Research Institute,The Cleveland Clinic, Cleveland, OH
2003 - Joint appointment in Department of Cardiovascular Medicine, Division of Medicine, Cleveland Clinic, Cleveland, OH
2004- Professor, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve Univ, Cleveland, OH
2004- CCF Adjunct Professor, Department of Chemistry , Cleveland State University, Cleveland, OH
2006- CCF Adjunct Professor, Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH
2015- Member Case Comprehensive Cancer Center
2017- Chair, Department of Molecular Medicine of the Cleveland Clinic Lerner College of Medicine, Case Western Reserve Univ, Cleveland, OH.
Awards and Honors:
1985-1987 National Research Service Award, National Institutes of Health
1989-1992 Investigatorship Award, American Heart Association, New York City Affiliate
1994-1999 Established Investigator, American Heart Association
1996-1997 President, New York Lipid Club
1999-2000 Founding President, New York Alzheimer Disease Research Society
2007 Outstanding Educator, Award of Excellence, Cleveland Clinic Lerner Research Institute
2009 Fellow of the American Association for the Advancement of Science, Section on Medical Sciences
2011 Co-Chair Atherosclerosis Gordon Research Conference
2001-2013 Leadership Committee member, Arteriosclerosis, Thrombosis, and Vascular Biology Council, of the American Heart Association
2013 Special Recognition Award in Arteriosclerosis from the Arteriosclerosis, Thrombosis, and Vascular Biology Council, of the AHA
2014 Chair, HDL Workshop
2014-2016 Geoffrey Gund Endowed Chair in Cardiovascular Research
2019 Award for Excellence in Education, Cleveland Clinic Lerner Research Institute
Research
Research Summary
We apply cell/molecular biology, biochemistry, and genetics/genomics to study three areas related to cardiovascular disease.
Atherosclerosis is the most common cause of cardiovascular disease and stroke. Atherosclerosis is initiated by high plasma cholesterol leading to monocyte entry into the artery wall and differentiation into macrophages, which take up lipoprotein cholesterol to become lipid engorged foam cells. We are identifying genes that alter atherosclerosis susceptibility in a mouse model and testing whether they play a role in coronary artery disease in humans.
The mechanism by which macrophages get rid of excess cholesterol is via a protective process known as reverse cholesterol transport. This involves moving cholesterol out of the cell via a membrane protein called ABCA1 and assembling this cholesterol onto apoAI to form HDL. We are studying how ABCA1 transfers lipids from the cell to apoAI. We are also studying how apoAI can become dysfunctional so that it can no longer participate in reverse cholesterol transport. We have created an apoAI variant that is resistant to becoming dysfunctional, which may be useful as a human therapeutic.
We are also examining the genetics and functional genomics of atrial fibrillation, a common arrhythmia that often leads to strokes. Together with Drs. Mina Chung, Dave Van Wagoner, and John Barnard, we have performed a genome wide association study for atrial fibrillation, and we are now working to determine how these common genetic variants act to alter susceptibility to this disease.
Our Team
Selected Publications
View publications for Jonathan Smith, PhD
(Disclaimer: This search is powered by PubMed, a service of the U.S. National Library of Medicine. PubMed is a third-party website with no affiliation with Cleveland Clinic.)
Wass, SY, Sun H, Tchou G, Liu N, Van Wagoner DR, Chung MK, Barnard J, Smith JD. Transcriptomic Insights into the Atrial Fibrillation Susceptibility Locus near the MYOZ1 and SYNPO2L Genes. (2024) Int. J. Mol. Sci. 2024, 25, 10309; https://doi.org/10.3390/ijms251910309.
Liu N, Hsu J, Mahajan G, Sun H, Laurita KR, Prasad SVN, Barnard J, Van Wagoner DR, Kothapalli CR, Chung MK, Smith JD. Common SYNE2 genetic variant associated with atrial fibrillation lowers expression of Nesprin-2a1 with downstream effects on nuclear and electrophysiological traits. (2024). Circ Genom Prec Med. 17:e004750. DOI: 10.1161/CIRCGEN.124.004750. NIHMS2024369.
Tchou G, Ponce-Balbuena D, Liu N, Gore-Panter S, Hsu J, Liu F, Opoku E, Brubaker G, Schumacher SM, Moravec CS, Barnard J, Van Wagoner DR, Chung MK, Smith JD. Decreased FAM13B expression increases atrial fibrillation susceptibility by regulating sodium current and calcium handling. (2023) JACC Basic Transl Sci. 10:1357-1378. doi: 10.1016/j.jacbts.2023.05.009. PMCID: PMC10714175.
Chepp V, Baker C, Kostiha S, Smith JD. The Molecular Medicine PhD Program Alumni Perceptions of Career Preparedness. (2022) PLoS One 17(11): e0275996. https://doi.org/10.1371/journal.pone.0275996. PMCID: PMC9671420.
Hai Q, Han J, Wells S, Smith JD. Efficient Method to Differentiate Mouse Embryonic Stem Cells into Macrophages in vitro. (2022) Bio-protocol 12:e4318. DOI:10.21769/BioProtoc.4318. PMCID: PMC8855084
Han J, Ritchey B, Opoku E, Smith JD. Fine mapping of the mouse Ath28 locus yields three atherosclerosis modifying sub-regions. (2021) Genes 13, 70. PMCID: PMC8774523.
Ritchey B, Hai Q, Han J, Barnard J, Smith JD. Genetic Variant in 3′ Untranslated Region of the Mouse Pycard Gene Regulates Inflammasome Activity. (2021) eLife 10:e68203. doi: 10.7554/eLife.68203. PMCID: PMC8248980.
Robinet P, Ritchey B, Lorkowski SW, Alzayed AM, DeGeorgia S., Schodowski E, Traughber, CA, Smith JD. Quantitative Trait Locus Mapping Identifies the Gpnmb Gene as a Modifier of Mouse Macrophage Lysosome Function. (2021) Scientific Rep 11: 10249. PMCID: PMC8119501.
Traughber CA, Opoku E, Brubaker G, Major J, Lu H, Wang Lorkowski S, Neumann C, Hardaway A, Chung YM, Gulshan K, Sharifi N, Brown JM, Smith JD. Uptake of high-density lipoprotein by scavenger receptor class B type 1 is associated with prostate cancer proliferation and tumor progression in mice. (2020) J Biol Chem. 295:8252-8261. PMCID: PMC7294086.
Lorkowski SW, Brubaker G, Li L, Li XS, Hazen SL, Smith JD. A Novel Cell-free Fluorescent Assay for HDL function: Low Apolipoprotein A1 Exchange Rate Associated with Increased Incident Cardiovascular Events. (2020) J Appl Lab Med 5:544-557. PMCID: PMC7192547.
Iacano AJ, Lewis H, Hazen JE, Andro H, Smith JD, Gulshan K. Miltefosine increases macrophage cholesterol release and inhibits NLRP3-inflammasome assembly and IL-1β release. (2019) Sci Rep 9:11128. doi: 10.1038/s41598-019-47610-w. PMCID: PMC6668382.
Lorkowski SW, Brubaker G. Gulshan K, Smith JD. Vacuolar ATPase Activity Required for ABCA1 Mediated Cholesterol Efflux. (2018) Arterioscler Thromb Vasc Biol 38:2615-2625. PMCID: PMC6209108.
Hsu J, Gore-Panter S, Tchou G, Castel L, Lovano B, Moravec CS, Pettersson GB, Roselli EE, Gillinov AM, McCurry KR, Smedira NG, Barnard J, Van Wagoner DR, Chung MK, Smith JD. The Genetic Control of Left Atrial Gene Expression Yields Insights into the Genetic Susceptibility for Atrial Fibrillation. (2018) Circ Genomics Prec Med 11:e002107. PMCID: PMC5858469.
Robinet P, Milewicz DM, Cassis LA, Leeper NJ, Lu HS, Smith JD. Consideration of Sex Differences in Design and Reporting of Experimental Arterial Pathology Studies: A Statement from the ATVB Council. (2018) Arterioscl Thromb Vasc Biol 38:292-303. PMCID: PMC5785439.
Gulshan K, Brubaker G, Conger H, Wang S, Zhang R, Hazen SL, Smith JD. PI(4,5)P2 is translocated by ABCA1 to the cell surface where it mediates apolipoprotein A1 binding and nascent HDL assembly, and it is carried on HDL. (2016) Circ Res 119:827-838. PMCID: PMC5026623.
Gore-Panter SR, Hsu J, Barnard J, Moravec CS, Van Wagoner DR, Chung MK, and Smith JD. PANCR, the PITX2 adjacent noncoding RNA, is expressed in human left atria and regulates PITX2c expression. (2016) Circ Arrhythm Electrophysiol 9:e003197. PMCID: PMC4719779.
Wang S, Brubaker G, Robinet P, Smith JD, Gulshan K. ORMDL orosomucoid-like proteins are degraded by free cholesterol loading induced autophagy. (2015) Proc Natl Acad Sci USA 112:3728-33. PMCID: PMC4378419.
Gulshan K, Brubaker G, Wang S, Hazen SL, Smith JD. Sphingomyelin Depletion Impairs Anionic Phospholipid Inward Translocation and Induces Cholesterol Efflux. (2013) J Biol Chem 288:37166-79. PMCID: PMC3873571.
Wang S, Gulshan K, Brubaker G, Hazen SL, Smith JD. ABCA1 mediates unfolding of apoAI N-terminus on the cell surface prior to lipidation and release of nascent HDL. (2013) Arterioscler Thromb Vasc Biol. 33:1197-1205. PMCID: PMC3701943.
Careers
Biomedical researcher and educator.
Research News
Dr. Smith will study risk genes and other genetic modifiers related to coronary artery disease due to atherosclerosis in an effort to identify therapeutic targets for future investigation.
Critical federal support will enable trainees to pursue greater research efforts into basic science and critical care medicine.
The four-year, competitive award will support three synergistic projects aimed at improving outcomes for patients with atrial fibrillation (AFib)
This study narrowed the focus to identify the specific genes and genetic variations associated with 12 identified chromosomal regions that can alter proper function of the left atrium, the top left chamber of the heart.