Federal Grant Award Summary

The National Heart, Lung, and Blood Institute (NHLBI) awarded The Johns Hopkins University a Project Grant totaling $248,999 (awarded July 5, 2026; completion date June 30, 2029) under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate the molecular mechanisms underlying heart failure with preserved ejection fraction (HFpEF). The research will examine how reduced hypusination of eukaryotic translation initiation factor 5A (EIF5A) impairs the translation of ubiquitin precursors and deubiquitinases, leading to free ubiquitin deficiency that contributes to HFpEF pathobiology. This work addresses a significant clinical gap, as HFpEF affects over half of heart failure patients yet remains poorly understood mechanistically.

The project will deliver research findings through two primary aims: Aim 1 will use polysome profiling, proteomics, and proteasome flux measurements in human myocardial tissue and cardiac-specific DHPS knockdown mice to test whether reduced EIF5A hypusination impairs translation of ubiquitin-related genes (UBC, USP9X, and USP7), resulting in hypo-ubiquitination and compromised protein quality control. Aim 2 will define mechanistic links between reduced EIF5A hypusination and impaired translation, focusing on difficult-to-translate amino acid motifs and the integrated ribosomal stress response. The research outputs will include peer-reviewed publications, experimental datasets, and potential therapeutic insights into ubiquitin supplementation as a treatment strategy for HFpEF.