alan-morrison-full

Assistant Professor of Medicine at the Warren Alpert Medical School of Brown University

Providence VA Medical Center
Research (151)
830 Chalkstone Ave.
Building 35, room 232
Providence, RI 02908

ph: (401) 273-7100 x6326
alan_morrison@brown.edu

Alan Morrison, MD

Bio

Alan R. Morrison, M.D., Ph.D., is Principal Investigator on the CardioPulmonary Vascular Biology COBRE Pilot study titled, “Therapeutic Targeting of IL-1β-Based Mechanisms in Calcific Aortic Valve Disease.” 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 CardioPulmonary Vascular Biology COBRE Pilot Award is to define the role of the small GTPase, Rac1, in a macrophage-mediated mechanism of aortic valve calcification. Calcific aortic valve disease is a common human disease with high mortality when the aortic valve becomes severely narrowed. There are no medical therapies that can prevent this disease process. Dr. Morrison’s project will shed light on an inflammatory mechanism that has potential to be absolutely critical to disease progression, highlighting new targets for the development of medical therapy.

Example: MicroCT Angiogram of New Artery Growth

COBRE Abstract

Calcific aortic valve disease (CAVD) is the most common cause of aortic stenosis in patients. The prevalence of aortic sclerosis, a precursor to stenosis, is approximately 25% of patients older than 65 years, and 10% of those patients will progress to severe, symptomatic stenosis. Pharmacotherapies aimed at slowing or reversing the disease process, including HMG-CoA reductase inhibitors (statins), have proven ineffective, and currently there is no medical therapy for CAVD. The current treatment paradigm targets symptomatic, severe stenosis (when mortality is high) with surgical aortic valve replacement, valvuloplasty, or transcatheter aortic valve replacement. The development of an effective medical treatment remains the major challenge for the field. My laboratory has developed a mouse model (Rac2-/-ApoE-/-) of accelerated inflammatory atherosclerotic calcification. The primary driver of progressive calcification is the cytokine, IL-1β, which promotes osteogenic transcription factor expression in vascular cells. The signaling mechanism responsible for increased IL-1β production in macrophages depends on a compensatory activation of Rac1. Preliminary data evaluating the aortic valve by histology and calcium-targeted imaging revealed evidence of aortic valve thickening and calcification, and treatment with the IL-1 receptor antagonist (IL-1ra) prevented progression of disease. The hypothesis is that macrophage Rac1-driven IL-1β expression is a critical mediator of the progression of CAVD. Using an established model of CAVD, we will identify macrophage Rac1 as a critical determinant of IL-1β expression and consequent progressive calcific aortic valve stenosis. Using diseased aortic valve tissue obtained at surgery from patients, we will define the relevance of this Rac-dependent IL-1β expression to human CAVD. Because inhibition of IL-1β, using IL-1ra or inhibitory monoclonal antibody, is approved for treatment of certain inflammatory diseases, we see this pilot study as critical to highlighting the mechanistic basis for inhibition of IL-1β as a novel preventive treatment strategy for patients afflicted with CAVD. Moreover, this study will establish the potential viability of Rac1-targeted inhibitors in treating this disease process.

Publications

Complete List of Dr. Morrison’s Published Work in MyBibliography:
http://www.ncbi.nlm.nih.gov/sites/myncbi/alan.morrison.1/bibliography/47842564/public/?sort=date&direction=ascending

Recent Manuscripts:

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.

Project Updates

He is the Principle Investigator of a 12-month pilot project form the CPVB COBRE entitled, “Therapeutic Targeting of IL-1β-Based Mechanisms in Calcific Aortic Valve Disease.”

Mentors

Dr. Gaurav Choudhary, MD
Associate Professor of Medicine, Alpert Medical School of Brown University Acting Associate Chief of Staff (Research) Providence VA Medical Center
E-mail: Gaurav_Choudhary@brown.edu
Website

Frank Sellke, MD
Chief of Cardiothoracic Surgery at the Alpert Medical School of Brown University and Rhode Island Hospital
E-mail: fsellke@lifespan.org
Website