(From left) Antonio Abbate, MD, PhD, Jeff Saucerman, PhD, and Stefano Toldo, PhD
Backed by a new four-year $3.1 million National Heart, Lung, and Blood Institute grant, School of Medicine researchers Antonio Abbate, MD, PhD, Jeff Saucerman, PhD, and Stefano Toldo, PhD, have initiated a new study to examine cell-specific low-density lipoprotein receptor 1 (LRP1) signaling and its impact in treatment of acute myocardial infarction (AMI).
Improving the treatment of AMI to prevent heart failure and death remains an urgent unmet medical need. Dr. Abbate and Dr. Toldo in the Department of Medicine’s Cardiovascular Division had previously identified and characterized LRP1 for its potential to protect the heart from ischemia-reperfusion injury after AMI. They also identified LRP1 agonists such as alpha1-antitrypsin and SP16 as means to reduce infarct size in animal models and in early-stage clinical trials. However, to date the roles of LRP1 in specific cell types and the downstream pathways that explain LRP1-mediated cardioprotection have been unclear.
To solve this challenge, Abbate and Toldo have teamed with biomedical engineer Jeff Saucerman in the UVA School of Medicine and UVA Engineering schools, who has experience untangling complex biological networks in the heart. Together, they have proposed an interdisciplinary approach to studying how LRP1 protects the heart, combining computational models, cell-based experiments, and mouse models that combine drugs and cell-specific deletions of LRP1.
Already, they discovered a surprising dichotomy in how LRP1 affects the heart. While post-AMI short-term LRP1 signaling in cardiomyocytes is beneficial, long-term LRP1 signaling in fibroblasts may be detrimental. They are now studying the signaling mechanisms responsible for this dichotomy as well as devising therapeutic strategies that leverage this knowledge.
Ultimately, they expect that these computational-experimental studies will provide improved therapeutic targeting opportunities for those with acute myocardial infarction and heart failure.
Filed Under: Research