Jonathan D. Smith,  Ph.D.

Jonathan D. Smith, Ph.D.

Staff

Geoffrey Gund Endowed Chair for Cardiovascular Research

Lerner Research Institute, 9500 Euclid Avenue, Cleveland, Ohio 44195

 

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.


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.


07/14/2021 |  

New $2.5M NIH Grant to Study the Genetics of Coronary Artery Disease

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.




06/15/2021 |  

Research Training Programs Receive $3 Million to Support Students and Early-Career Scientists

Critical federal support will enable trainees to pursue greater research efforts into basic science and critical care medicine.