Jonathan D. Smith, Ph.D.
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.
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.
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.
Berisha SZ, Brubaker G, Kasumov T, Hung KT, DiBello PM, Huang Y, Li L, Willard B, Pollard KA, Nagy LE. Hazen SL, Smith JD. HDL from ApoA1 Transgenic Mice Expressing the 4WF Isoform Is Resistant to Oxidative Loss of Function. (2015) J Lipid Res 56:653-64 . PMCID: PMC4340312.
Gore-Panter SR, Hsu J, Hanna P, Gillinov AM, Pettersson G, Newton DW, Moravec CS, Van Wagoner DR, Chung MK, Barnard J, and Smith JD. Atrial fibrillation associated chromosome 4q25 variants are not associated with PITX2c expression in human adult left atrial appendages. (2014) PlosOne e86245. PMCID: PMC3899225.
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.
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.