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

项目总结/摘要 极长链酰基辅酶A脱氢酶缺乏症（VLCADD）持续引起顽固性心肌病 导致心力衰竭和儿童死亡一个显著的未满足的需求是阐明心脏特异性 为了开发能够预防疾病进展的新的治疗策略， 过早死亡虽然能量缺乏导致减少生产ATP从脂质燃料 已经被认为是VLCADD相关病理的驱动因素，但不太可能解释VLCADD的全部谱。 组织缺损本文提供的初步数据表明，脂毒性在很大程度上是由 神经酰胺的积累是VLCADD诱导心力衰竭的主要原因， 治疗这种疾病的治疗目标。在这个奖学金申请中提出的工作将批判性地评估 一类脂毒性脂质物质（称为神经酰胺）作为VLCADD诱导的心力衰竭驱动因素的作用。 越来越多的证据表明，升高的神经酰胺会导致人类心肌病和心力衰竭 和啮齿类动物，心脏功能随着神经酰胺的消耗而改善。事实上，以前的研究表明， 神经酰胺在VLCADD小鼠模型的心脏组织中升高。然而，目前仍不清楚， 神经酰胺积累在VLCADD患者心力衰竭的发展中起着因果作用。我们的初步 数据证实神经酰胺在VLCADD的体外和体内模型中均升高， 神经酰胺的合成改善了VLCADD的许多脂毒性和代谢缺陷， 神经酰胺合成改善VLCADD小鼠模型中的心脏肥大和心脏功能。的 拟议的项目将确定神经酰胺是否是VLCADD诱导的心力衰竭的介质， VLCADD患者心脏病风险的生物标志物。在目标一中，我们将使用神经酰胺的体内方法 减少或诱导，以评价VLCADD模型中心力衰竭的特征。目标二中提议的研究将 确定血浆神经酰胺是否是VLCADD患者心脏病风险的有效生物标志物 使用由Nicola医生在知情同意的情况下采集的去识别VLCADD患者（IRB_00007551）的血浆 Longo在犹他州大学的临床团队和我们的合作者， 匹兹堡这将是第一个研究VLCADD中神经酰胺及其在心力衰竭中作用的项目 在这个病人群体中，我们的研究结果将为新的应用奠定基础 靶向神经酰胺作为VLCADD心力衰竭关键驱动因素的药物策略。此外，委员会还认为， 完成拟议的研究将大大丰富申请人的博士前培训，掌握技术 技能和发展作为一个年轻的科学家追求独立的研究生涯。

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.