Diseases linked to atherosclerosis, such as coronary artery disease, are the leading cause of death in the United States. Healthy arteries are elastic, but as we age, fats, cholesterol, and other substances form plaque in the arteries. This build up can narrow artery walls, block blood flow, or can burst, which may lead to blood clotting. Although aging is the strongest known risk for atherosclerosis, there is a significant gap in understanding how aging promotes the condition.
Daniel Tyrrell, Ph.D., an assistant professor in the Division of Molecular and Cellular Pathology, recently received funding from the National Institutes of Health’s National Heart, Lung, and Blood Institute for his project, titled, “Age-associated cytotoxic T cell mechanisms of atherosclerosis”. The five year, $3 million R01 will run through March 2031.
“We found that later in life, a specific type of cytotoxic T cell expresses an enzyme called granzyme K, which accumulates in atherosclerotic lesions,” Tyrrell said. “We’re trying to figure out what drives the buildup of this type of cell in old age, and how granzyme K may be driving atherosclerosis.”
In addition to granzyme K, Tyrrell found a unique T cell population accumulated in elderly humans and mouse models, known as age-associated T cells. Age-associated T cells make up more than 55% of all T cells in atherosclerotic plaques, however its contribution to atherosclerosis has not been explored. Tyrrell’s research team will test their hypotheses by using a combination of in vitro and in vivo mouse models.
“Our goal in this project is two-fold,” Tyrrell said. “We want to determine what drives the accumulation of age-associated T cells in old age and how granzyme K may be driving atherosclerosis.”
Tyrrell’s collaborators on the project include Silvio Litovsky, M.D. in the Department of Pathology, Allan Zajac, Ph.D. in the Department of Microbiology, and Jianmei Wu Leavenworth, M.D., Ph.D. in the Department of Neurosurgery.
“We’re hopeful that the outcome of this study will provide valuable insights into the roles of both granzyme K and age-associated T cells in atherosclerosis, which could lead to the development of novel therapeutic strategies for coronary artery disease in older adults.