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

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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.