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

项目摘要/摘要 超长链酰辅酶A脱氢酶缺乏症(VLCADD)继续导致顽固性心肌病 随之而来的是心脏衰竭和儿童死亡。一个重要的未得到满足的需求是阐明心脏特异的 侮辱推动疾病发展的人，以开发能够预防的新治疗策略 过早死亡。虽然由于脂肪燃料产生的三磷酸腺苷减少而导致的能量不足 已被牵连为VLCADD相关病理的驱动因素，但不太可能解释 组织缺陷。这里提供的初步数据表明，脂毒性在很大程度上是由 神经酰胺的积聚是VLCADD诱发心力衰竭的主要因素，并阐明了其潜在的作用 治疗这种疾病的治疗目标。在此奖学金申请中提出的工作将进行批判性评估 一类脂毒性脂质物种，称为神经酰胺，作为VLCADD诱导的心力衰竭的驱动因素的作用。 越来越多的证据表明，神经酰胺升高会导致人类的心肌病和心力衰竭 和啮齿动物，随着神经酰胺的枯竭，心脏功能得到改善。事实上，之前的研究表明 VLCADD模型小鼠心脏组织中神经酰胺含量升高。不过，目前还不清楚 神经酰胺蓄积在VLCADD患者发生心力衰竭中起因果作用。我们的预赛 数据证实，神经酰胺在VLCADD的体外和体内模型中均升高，体外抑制 神经酰胺合成改善VLCADD的许多脂毒性和代谢缺陷，并在体内抑制 神经酰胺合成改善VLCADD小鼠模型的心肌肥厚和心功能。这个 拟议的项目将确定神经酰胺是否是VLCADD诱导的心力衰竭的媒介，以及是否有效 VLCADD患者心脏病风险的生物标志物。在第一个目标中，我们将使用体内神经酰胺的方法。 在VLCADD模型中评估心力衰竭特征的还原或诱导。在目标二中提出的研究将 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 使用尼古拉博士知情同意收集的不明原因的极大冠脉综合征患者(IRB_00007551)的血浆 犹他州大学隆戈的临床团队和我们的合作者，加州大学的曾傑瑞·沃克利博士 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的作用的项目。 在这个患者群体中观察到。我们的发现将为小说的应用奠定基础 将神经酰胺作为VLCADD心力衰竭的关键驱动因素的药物策略。此外， 完成拟议的研究将极大地丰富申请人的博士前培训，掌握技术 作为一名追求独立研究事业的年轻科学家，他的技能、技能和发展。

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.