Therapeutic potential of nucleotide supplementation in cardiac repair

The National Heart Lung and Blood Institute awarded the Beckman Research Institute of the City of Hope $813,810 on September 1, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to conduct research on nucleotide supplementation as a treatment strategy for ischemic heart disease and myocardial infarction.

The project investigates the role of nucleotide balance in cardiomyocyte proliferation and aims to apply these findings for cardiac repair using large animal models. Preliminary data indicate that select nucleotide treatments increase cardiomyocyte proliferation in cell culture and improve cardiac function in mice following myocardial infarction. The research will test the hypothesis that nucleotide imbalance inhibits cardiomyocyte proliferation, while restoring this balance stimulates cellular replication and enables direct improvement of myocardial function in ischemic heart disease.

Performance of work occurs in Irwindale, California. The period of performance extends from September 1, 2026, through April 30, 2030. This is a Project Grant, a standard assistance type for hypothesis-driven biomedical research under the NIH competitive grant program.

Abstract

Ischemic heart disease is a leading cause of morbidity and mortality worldwide. Myocardial infarct size is the major determinant of the severity of functional impairment and the risk of subsequent heart failure. Current guideline-directed therapies primarily target neurohormonal modulation to limit adverse remodeling; however, emerging data suggest that heart failure mortality continues to rise, underscoring the urgent need for therapies that directly improve myocardial function. Despite urgent clinical needs, effective treatment to restore injured myocardium is not available. The long-term goal of this project is to uncover novel mechanisms of cardiomyocyte proliferation and explore nucleotide supplementation as a novel treatment strategy for ischemic heart disease. Since cardiomyocytes largely lose their proliferative capacity early during development, understanding factors governing their cell fate is crucial to make cardiac repair a reality. Recent evidence suggests that nucleotide balance is key to cell growth and proliferation, while an imbalance of cellular nucleotide levels inhibits cell replication due to heightened oxidative stress. Therefore, the main objective of this study is to determine the role of nucleotide balance in cardiomyocyte proliferation and to apply this finding for cardiac repair using large animal models. Preliminary findings suggest that select nucleotide treatments increase cardiomyocyte proliferation in cell culture in vitro and improve cardiac function in mice following MI in vivo. Based on these findings, a central hypothesis has been formulated that nucleotide imbalance inhibits cardiomyocyte proliferation, while restoring this balance stimulates cellular replication. To test this hypothesis, two specific aims have been proposed. In specific aim 1, the molecular mechanisms by which nucleotide balance promotes cardiomyocyte proliferation will be investigated by focusing on proliferative signaling and metabolic pathways, respectively. Multi-omic analyses will be conducted at transcriptomic, epigenetic, and metabolomic levels. In specific aim 2, the therapeutic effects of nucleotide balance on ischemic heart disease will be assessed using mouse models of myocardial I/R. In addition, cardiac- targeted nanoparticle delivery of nucleotides will be explored to improve therapeutic efficacy in both murine and porcine models. Successful completion of the proposed specific aims in this proposal will define the role of nucleotide balance in cardiac proliferation, develop and test nucleotide-based regenerative therapies for ischemic heart disease, and provide preclinical evidence for a novel targeted therapeutic approach to restore myocardial function.