Grants and Contracts Details
Description
SUMMARY
This proposal explores the hypothesis that very long chain ceramides serve as a causal mediator in the structural
and functional changes which underlie diastolic heart failure. Moreover, this suggests a rare opportunity for
intervention for a disease that has limited evidence-based therapies. The idea is predicated upon data presented
herein showing that the genetic deletion of a ceramide synthesis enzyme, dihydroceramide desaturase 1 (Des1),
prevents hypertrophy and impairments in diastolic function in 2 distinct mouse models of HFpEF. The theory is
further supported by untargeted lipidomics from HFpEF patients, which demonstrate ceramides as the most
upregulated lipids. Moreover, cardiac-specific ablation of acid ceramidase, is sufficient to drive ceramide
accumulation and diastolic dysfunction. Administration of a pharmacological inhibitor of ceramide biosynthesis
to rodents preserves diastolic function and prevents fibrosis and hypertrophy, suggesting therapeutic potential if
safe, effective ceramide synthesis inhibitors are identified. We will determine if ceramides are necessary and
sufficient mediators of diastolic heart failure that can be targeted for therapeutic intervention. We will evaluate
our hypotheses through the following Aims:
• First, we will determine the effects of genetic induction or reduction of ceramides selectively in
cardiomyocytes in mouse models of HFpEF.
• Second, we will determine the efficacy of Des1 antagonism or ablation as a therapeutic approach for
the treatment or prevention of HFpEF.
• Third, we will elucidate the mechanisms linking ceramides to cardiac fibrosis and mitochondrial
dysfunction using cells, mice and human tissues.
Findings obtained from these studies could uncover new nutrient-sensing regulatory mechanisms that modulate
mitochondrial function, cardiomyocyte survival, fibrosis, and hypertrophy. Moreover, the translational component
of this work could propel the development of promising therapeutics for preventing or treating HFpEF.
Status | Active |
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Effective start/end date | 7/17/24 → 6/30/29 |
Funding
- University of Utah: $40,000.00
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