Sunday, May 11, 2025
5/11/2025
The role of PAR2 and HuR in programming atherosclerotic vascular smooth muscle cells - PROJECT SUMMARY/ABSTRACT Coronary artery disease (CAD), the result of atherosclerosis formation, is the leading cause of death globally resulting in approximately 679,000 annual deaths or the equivalent to every one in five deaths occurring in the United States. This number is expected to increase as comorbidities of CAD diagnosed in patients continues to rise. Currently, statins, which lowers the amount of circulating lipids, are the gold standard of preventing CAD in patients with a concomitant diet and exercise regimen. After decades of steadily improving mortality rates, overall trends have begun to plateau and current medications provide only modest absolute incremental benefits from atherosclerotic plaque rupture and resultant myocardial infarction, stoke, and heart failure. Our laboratory has previously demonstrated the G-protein coupled receptor, PAR2, is augmented in both murine and human atherosclerotic plaques. Moreover, studies have demonstrated increased Human Antigen R (HuR) expression at sites of vessel injury, with the potential to bind and stabilize PAR2 mRNA in these inflammatory conditions. Though we know PAR2 contributes to the formation of atherosclerosis, the mechanism(s) in which PAR2 mediates atherosclerosis formation and the role of HuR in atherosclerosis are still unknown. Understanding the molecular mechanisms in which PAR2 and HuR contributes to the progression of atherosclerosis could give new insight into potential targets of therapeutics that could improve the outcomes of CAD patients and put a halt to the diminishing returns of old therapeutics. The primary goal of this proposal is to investigate the mechanisms by which PAR2 and HuR interact and their contributions, both independently and dependently, to atherosclerosis development. Using data previously collected in our lab, we know that the contributions of PAR2 in atherosclerosis derive from a non-hematopoietic cell type, such as vascular smooth muscle cells (VSMCs). Thus, we hypothesize that activation of PAR2 in VSMCs relocates HuR to the cytosol where it binds and stabilizes Par2 mRNA, upregulating PAR2 expression and further progressing atherosclerosis. This hypothesis will be using two specific aims and several mouse models that consist of PAR2 and HuR genetic mutants, specifically in VSMCs (aim 1 and aim 2 respectively). We will also use a variety of in vitro experiments to observe HuR binding PAR2 mRNA (aim 2) as well as investigate the role of PAR2 in VSMC dedifferentiation (aim 1), which recent literature has shown the contributions of VSMC dedifferentiation to the progression of atherosclerosis. The long-term objective of this study is to further elucidate the role of PAR2 in atherosclerosis and, if successful, will advance our knowledge of the development and progression of this disease. These results may also positively impact the field and give sight to potential targets to develop new therapies for CAD patients.
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