Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Reduced hypusination of EIF5A impairs free ubiquitin generation resulting in the development of HFpEF

Award Number: R00HL179380
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/05/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2029

Group Awards By:

View Award Description

Reduced hypusination of EIF5A impairs free ubiquitin generation resulting in the development of HFpEF - Heart Failure with Preserved Ejection Fraction (HFpEF) affects over half of heart failure patients, yet its mechanisms remain poorly understood. Proteomic analyses of HFpEF myocardium show reduced translation pathways and markedly decreased eIF5A hypusination (eIF5A-Hyp). Despite increased spermidine, reduced DHPS suggests a bottleneck limiting eIF5A-Hyp. Cardiac-specific DHPS knockdown mice (ciDHPS-KD) exhibit an HFpEF phenotype. Ribosome profiling in cardiomyocytes with inhibited eIF5A-Hyp identifies ubiquitination-related genes as inefficiently translated, including the ubiquitin precursor UBC and the deubiquitinase USP9X. Free ubiquitin is reduced in human HFpEF myocardium and eIF5A-Hyp-deficient cells. Recombinant ubiquitin supplementation reduces toxicity and partially restores mitochondrial respiration, with proteomic evidence of recovery. USP9X protein and total ubiquitination are also decreased across HFpEF and eIF5A-Hyp-deficient models, independent of increased degradation, and ubiquitin supplementation mitigates toxicity in USP9X-deficient cells. This project hypothesizes that reduced eIF5A hypusination impairs translation of ubiquitin precursors and deubiquitinases, limiting the free ubiquitin pool contributing to HFpEF pathobiology. Aim 1 tests whether reduced eIF5A-Hyp impairs translation of UBC, USP9X, and USP7, leading to free ubiquitin deficiency, hypo-ubiquitination, and impaired protein quality control. This will be assessed using polysome profiling, proteomics, and measures of proteasome flux, ubiquitin levels, and protein aggregation in human myocardium and ciDHPS-KD mice. Aim 2 defines mechanisms linking reduced eIF5A-Hyp to impaired translation, focusing on hard-to-translate amino acid motifs and the integrated ribosomal stress response. UBC mutants with substituted motifs restore expression under reduced eIF5A-Hyp conditions, and polysome profiling shows stalled translation of UBC and USP9X. Bypassing the stress response restores global translation but not target-specific translation or ubiquitination. Aim 3 tests this pathway in vivo by determining whether reducing the free ubiquitin pool via UBC knockdown induces HFpEF, and whether restoring it—through ubiquitin overexpression or enhancing DHPS activity with spermidine—rescues the phenotype in ciDHPS-KD mice. Together, these studies define a previously unrecognized mechanism linking impaired protein translation to ubiquitin-dependent protein quality control in HFpEF.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $248,999 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	3	7/16/2026	EXTENSION WITH OR WITHOUT FUNDS	$248,999
														Subtotal = $248,999

Grand Total All Awards = $248,999

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Reduced hypusination of EIF5A impairs free ubiquitin generation resulting in the development of HFpEF

Award Number: R00HL179380

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/05/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2029

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer