# Ceramides as Novel Mediators of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency-Induced Heart Failure.

> **NIH NIH F31** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $26,269

## Abstract

PROJECT SUMMARY/ABSTRACT
Very long-chain acyl-coA dehydrogenase deficiency (VLCADD) continues to cause unyielding cardiomyopathy
with consequent heart failure and childhood death. A significant unmet need exists to elucidate cardiac-specific
insults that drive disease progression in order to develop novel therapeutic strategies capable of preventing
premature death. Although energy deficiency resulting from the diminished production of ATP from lipid fuels
has been implicated as a driver of VLCADD-associated pathologies, it is unlikely to explain the full spectrum of
tissue defects. Preliminary data presented herein suggest that lipotoxicity—mediated in large part by the
accumulation of ceramides—is a major contributor to VLCADD-induced heart failure and elucidates potential
therapeutic targets to treat this disease. The work proposed in this fellowship application will critically evaluate
the role of a class of lipotoxic lipid species, termed ceramides, as drivers of VLCADD-induced heart failure.
Mounting evidence reveals that elevated ceramides contribute to cardiomyopathy and heart failure in humans
and rodents and that cardiac function improves with ceramide depletion. Indeed, previous studies demonstrate
that ceramides are elevated in cardiac tissue from VLCADD mouse models. Still, it remains unknown whether
ceramide accumulation plays a causal role in developing heart failure in patients with VLCADD. Our preliminary
data confirm that ceramides are elevated in both in vitro and in vivo models of VLCADD, that in vitro inhibition of
ceramide synthesis improves many lipotoxic and metabolic deficits of VLCADD, and that in vivo inhibition of
ceramide synthesis improves cardiac hypertrophy and cardiac function in VLCADD mouse models. The
proposed project will determine if ceramides are mediators of VLCADD-induced heart failure and effective
biomarkers for cardiac disease risk in VLCADD patients. In Aim One, we will use in vivo methods of ceramide
reduction or induction to evaluate features of heart failure in VLCADD models. Studies proposed in Aim Two will
determine whether plasma ceramides are an effective biomarker for cardiac disease risk in VLCADD patients
using plasma from de-identified VLCADD patients (IRB_00007551) collected with informed consent by Dr. Nicola
Longo’s clinical team at the University of Utah and by our collaborator, Dr. Jerry Vockley, at the University of
Pittsburgh. This will be the first project investigating ceramides in VLCADD and the role they play in heart failure
observed in this patient population. Our findings will lay the groundwork for the application of novel
pharmaceutical strategies targeting ceramides as key drivers of heart failure in VLCADD. Furthermore,
completion of the proposed studies will greatly enrich the applicant’s pre-doctoral training, mastery of technical
skills, and development as a young scientist pursuing an independent research career.

## Key facts

- **NIH application ID:** 11051763
- **Project number:** 5F31HL170478-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Marie Kristine Norris
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $26,269
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11051763

## Citation

> US National Institutes of Health, RePORTER application 11051763, Ceramides as Novel Mediators of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency-Induced Heart Failure. (5F31HL170478-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11051763. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*