Alan Morrison, MD, PhD
Providence VA Medical Center
830 Chalkstone Ave.
Building 35, room 232
Providence, RI 02908
Alan R. Morrison, M.D., Ph.D. is Principle/Junior Investigator on CPVB COBRE project “IL-1β Signaling Promotes Atherosclerotic Calcification and Cardiovascular Risk”. He is also a cardiologist at the Providence VA Medical Center He is also a cardiologist at the Providence VA Medical Center with a VA Career Development Award and Assistant Professor of Medicine at the Alpert Medical School of Brown University.
Dr. Morrison is a graduate of the University of Massachusetts at Amherst and the University of Massachusetts Medical School, where he obtained a combined M.D./Ph.D. in Biomedical Sciences. He trained in Internal Medicine at Yale University School of Medicine and Yale New Haven Hospital and did a Cardiovascular Medicine Fellowship at Yale University School of Medicine. In addition, Dr. Morrison received training and certifications in advanced cardiovascular imaging, including Nuclear Cardiology and Cardiac CT. Upon completion of his clinical training, he returned to the research bench and completed a postdoctoral research fellowship in vascular biology under the mentorship of Dr. Jeffrey Bender at Yale. Dr. Morrison was appointed to Assistant Professor of Medicine at Yale School of Medicine in 2014. He was appointed to Assistant Professor of Medicine at Alpert Medical School of Brown University in 2016.
Dr. Morrison has combined careers in clinical cardiovascular medicine, teaching, and vascular biology research. He maintains a strong interest in developing basic research projects that have translational impact for clinical disease. Basic science research interests include mechanisms of immune-mediate vascular remodeling focusing of areas where macrophages direct the biologic processes of arteriogenesis, vascular calcification, and pulmonary arterial hypertension. His laboratory has a number of active studies defining novel macrophage-dependent signaling mechanisms that modulate these processes, using a diverse array of techniques in molecular biology, immunobiology, small animal genetics, and vascular biology.
The goal of Dr. Morrison’s project is to define cellular specific upregulation of the expression of key inflammasome signaling components, IL-1β, IL-1R and IL-1R signaling components, as well as an osteogenic gene program in atherosclerotic plaques as they begin to calcify.
Example: MicroCT Angiogram of New Artery Growth
Coronary artery disease from calcific atherosclerosis is the leading cause of morbidity and mortality in the world. The calcium composition of atherosclerotic plaque has predictive value in terms of cardiovascular events. Inflammation is likely a key mediator of vascular calcification, but immune signaling mechanisms that promote this process are minimally understood. Recently, the inflammatory cytokine, IL-1β, was identified to be increased in calcifying atherosclerotic aortas from ApoE-/- background mice fed a high fat diet. Moreover, plaque and serum from mice with progressive calcification demonstrated increased expression of IL-1β. Treatment with the IL-1 receptor antagonist inhibited atherosclerotic calcification. IL-1β expression was a key driver of vascular smooth muscle cell calcium deposition by its ability to promote expression of the osteogenic transcription factors, RUNX2, SOX9, OSX and MSX2. Bone marrow transplantation confirmed that progressive calcification of plaque is attributable to the hematopoietic compartment. Several key questions remain: 1) are macrophages the key cellular source of plaque IL-1β during atherosclerotic calcification; 2) do vascular smooth muscle cells take on an inflammatory phenotype to promote plaque IL-1β expression; 3) what are the effects of IL-1 receptor signaling on both plaque macrophages and vascular smooth muscle cells; 4) how does IL-1 receptor signaling lead to an osteogenic gene program; and 5) can IL-1β serve as a biomarker of progressive calcification in patients with coronary artery disease. Preliminary data demonstrated that macrophages appear associated with expression of IL-1β in plaque, and consequently, IL-1β signaling through its receptor may play an autocrine positive feedback role in promoting further IL-1β expression by macrophages. Vascular smooth muscle cells, in contrast, appear to play a responsive role to IL-1β signaling by activating an osteogenic gene program. However, global deletion of the IL-1 receptor demonstrated conflicting data about whether nonspecific inhibition of IL-1β signaling can protect against plaque vulnerability, indicating further study to delineate cell-specific contributions in this pathway is required. The hypothesis is that macrophage expression of IL-1β in atherosclerotic plaque and consequent vascular cell IL-1 receptor signaling lead to inflammatory atherosclerotic calcification resulting in increased risk of plaque rupture. Aim 1 will define macrophage IL-1β expression as the critical to inflammatory atherosclerotic calcification. Aim 2 will determine the respective roles of macrophage and smooth muscle cell IL-1 receptor signaling in inflammatory atherosclerotic calcification and osteogenic transcription factor expression. Aim 3 will validate serum IL-1β as a critical biomarker of progressive coronary artery calcification in patients. Confirming that a macrophage IL-1β signaling axis is a central mechanism in inflammatory atherosclerotic calcification in preclinical and translational studies paves the way for developing a novel therapeutic strategy aimed at treating risk in coronary artery disease, as anti-IL-1β therapies have been developed and are actively under investigation.
Complete List of Dr. Morrison’s Published Work in MyBibliography:
A.R. Morrison, T.O. Yarovinsky, B.D. Young, F. Moraes, T.D. Ross, N. Ceneri, J. Zhang, Z.W. Zhuang, A.J. Sinusas, R. Pardi, M.A. Schwartz, M. Simons, J.R. Bender, “Chemokine-coupled beta2 integrin-induced macrophage Rac2-Myosin IIA interaction regulates VEGF-A mRNA stability and arteriogenesis,” The Journal of Experimental Medicine 211 (10): 1957-1968, September 1, 2014.
G. Bailey, J. Meadows, A.R. Morrison, “Imaging Atherosclerotic Plaque Calcification: Translating Biology,” Current Atherosclerosis Reports 2016 August;18(8):51.
N. Ceneri, L. Zhao, B.D. Young, A. Healy, S. Coskun, H. Vasavada, T.O. Yarovinsky, K. Ike, R. Pardi, L. Qin, L. Qin, G. Tellides, K. Hirschi, J. Meadows, R. Soufer, H.J. Chun, M. Sadeghi, J.R. Bender, A.R. Morrison. Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage Interleukin-1beta Production. Arteriosclerosis, thrombosis, and vascular biology. 2016.
Gaurav Choudhary, MD
Associate Professor of Medicine, Alpert Medical School of Brown University Acting Associate Chief of Staff (Research) Providence VA Medical Center
NIH NHLBI R01
Title: Development of a Rac-targeted Therapeutic Strategy for Treatment of Calcific Atherosclerosis
Project period: 1/15/2018 – 11/30/2022
Ocean State Research Institute
Providence VA Medical Center
830 Chalkstone Avenue
Providence RI 02908
Research Funded by
Research reported in this website was supported by the National Institute of General Medical Science of the National Institutes of Health under grant number P20GM103652.