Luke Brewster Receives NIH R01 to Study Pathways That Cause PAD

October 2018

"As patients with cardiovascular problems continue to live longer, we will see an uptick in peripheral arterial disease, or PAD," says Emory vascular surgeon-researcher Luke Brewster, MD, PhD. PAD is a condition characterized by stiffened arteries that can double cardiovascular mortality and lead to amputation. "However, we are getting closer to uncovering the unique molecular signatures that predispose the arteries of patients with PAD to lose elasticity and have restricted blood flow. Our objective is to discover ways of manipulating these pathways to limit disease progression, improve limb salvage, and restore quality of life for these patients."

Dr. Brewster is completing an NIH-funded K08 in which he identified the role played by the protein thrombospondin-1 (TSP-1) in stimulating the progressive collagen deposition that can stiffen arteries, in turn leading to PAD. He also found that TSP-1 production can be increased by the unique signaling pathway created by the combination of arterial stiffness and irregular blood flow.

Armed with a new, five-year NIH R01 grant, Dr. Brewster will serve as Principal Investigator on a project that will build upon the K08's discoveries to reach a wider understanding of the clinically relevant pathways in PAD. Specifically, Dr. Brewster and his colleagues have identified molecular mediators of a unique PAD signature from stiff arteries that are exposed to pathologic blood flow. In this study, the team will develop and test therapeutic strategies to limit both arterial stiffening and narrowing from focal atherosclerotic plaque. Human tissue from patients with PAD will then be used to validate these pathways in clinically relevant arteries.

Dr. Brewster's co-investigators and mentors on the grant are faculty from the Wallace Coulter Department of Biomedical Engineering at Georgia Tech and Emory School of Medicine, and include Hanjoong Jo, PhD, an expert in endothelial cell mechanobiology and atherosclerosis; Sandeep Kumar, PhD, who focuses on gene network regulation; and vascular mechanics and modeling specialists Rudolph Gleason, Jr., PhD, and Anastassia Pokutta-Paskaleva, PhD.

"Positive results will be useful in developing novel PAD therapeutics that disrupt these pathways and improve arterial health in our patients," says Dr. Brewster.

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