Alternative polyadenylation regulation in cardiac fibrosis

The National Institutes of Health National Heart Lung and Blood Institute awarded The Methodist Hospital Research Institute $789,693 on August 15, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837, R01HL172902) to investigate alternative polyadenylation regulation in cardiac fibrosis.

The research examines how depletion of the alternative polyadenylation regulator NUDT21 drives three-prime untranslated region shortening of profibrotic transcripts and contributes to pathological cardiac fibrosis. The work tests the hypothesis that miR-27b-mediated suppression of NUDT21 drives alternative polyadenylation remodeling and fibrotic activation, while restoring NUDT21 reverses fibroblast activation and promotes myocardial recovery. The recipient will determine cellular and molecular mechanisms of NUDT21-dependent alternative polyadenylation using transcriptomic, biochemical, and in vivo genetic approaches; evaluate how upstream signaling pathways and miR-27b regulate NUDT21 expression; and assess the therapeutic potential of restoring NUDT21 function or blocking its upstream repression. The work builds toward translational applications in precision, disease-modifying therapies for heart failure and establishes a framework for treating other fibroblast-driven diseases.

Performance occurs in Houston, Texas, through April 30, 2031. The assistance type is a project grant.

Abstract

Heart failure remains a leading cause of mortality worldwide, with cardiac fibrosis recognized as a major pathological driver of disease progression. Although transcriptional mechanisms governing fibroblast activation have been widely studied, the role of post-transcriptional regulation-particularly alternative polyadenylation (APA)-remains poorly understood. APA modulates gene expression by altering 3′ untranslated region (3′UTR) length, thereby influencing mrna stability, translation efficiency, and microrna binding. This process plays a critical role in tissue remodeling and stress adaptation. Our goal is to determine the molecular mechanisms through which APA remodeling governs fibroblast phenotype and fibrotic gene expression in the heart. The objective of this proposal is to investigate how depletion of the APA regulator nudix hydrolase 21 (NUDT21) drives 3′UTR shortening of profibrotic transcripts and contributes to pathological cardiac fibrosis. Our central hypothesis is that MIR-27B-mediated suppression of NUDT21 drives APA remodeling and fibrotic activation, while restoring NUDT21 reverses fibroblast activation and promotes myocardial recovery. To test this hypothesis, we will determine the cellular and molecular mechanisms of NUDT21-dependent APA remodeling using transcriptomic, biochemical, and in vivo genetic approaches. We will also determine how upstream signaling pathways and MIR-27B regulate NUDT21 expression and evaluate the therapeutic potential of restoring NUDT21 function or blocking its upstream repression. Building on our published patent on APA modulation in heart failure and validated AAV platforms, this work offers a clear translational path toward precision, disease-modifying therapies for heart failure. IT also establishes a framework for treating other fibroblast-driven diseases and lays the foundation for RNA-based interventions that could transform heart failure management.