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

神经酰胺作为极长链酰基辅酶A脱氢酶缺乏引起的心力衰竭的新型介体。

基本信息

批准号：
10747561
负责人：
Marie Kristine Norris
金额：
$ 4.34万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10747561
关键词：
Age Apoptosis Biological Markers Body Weight Brain natriuretic peptide Cardiac Cardiomyopathies Cardiovascular Diseases Cells Ceramides Cessation of life Child Child Mortality Childhood Clinic Clinical Cre lox recombination system Data Defect Development Disease Disease Progression Doxycycline Dyslipidemias Echocardiography Enzymes Fatty Acids Fatty acid glycerol esters Fellowship Fibrosis Genes Goals Heart Heart Diseases Heart Hypertrophy Heart failure Histopathology Human Impairment In Vitro Informed Consent Institutional Review Boards Knockout Mice Knowledge Length Lipids Logistic Regressions Long-Chain-Acyl-CoA Dehydrogenase Measures Mediating Mediator Metabolic Metabolism Methods Mission Mitochondria Modeling Modification Morphology Mus Myocardial dysfunction Myosin Heavy Chains Neonatal Screening Obesity Pathogenesis Pathology Pathway interactions Patients Pharmacologic Substance Phenotype Plasma Play Production ROC Curve Research Risk Risk Marker Rodent Role Sampling Scientist Severity of illness Signal Transduction Tamoxifen Technical Expertise Testing Tissues Training Transgenes Transgenic Mice Transgenic Organisms United States National Institutes of Health Universities Utah VLCAD deficiency VLCADD patient Weight Work acylcarnitine cardiovascular risk factor career clinical biomarkers disability early experience experience fatty acid oxidation heart disease risk heart function human disease improved in vivo in vivo Model lipidomics long chain fatty acid mortality mouse model new therapeutic target novel novel therapeutic intervention overexpression oxidation patient population pre-doctoral premature prevent promoter serine palmitoyltransferase sex therapeutic target tibia transcriptomics

项目摘要

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.

项目概要/摘要极长链酰基辅酶A脱氢酶缺乏症（VLCADD）继续导致顽固性心肌病随之而来的心力衰竭和儿童期死亡。阐明心脏特异性的需求存在重大未满足的需求促进疾病进展的损伤，以开发能够预防的新治疗策略过早死亡。尽管脂质燃料产生的 ATP 减少导致能量不足已被认为是 VLCADD 相关病理的驱动因素，但它不太可能解释所有的症状组织缺陷。本文提供的初步数据表明，脂毒性很大程度上是由神经酰胺的积累——是 VLCADD 诱发心力衰竭的主要原因，并阐明了潜在的治疗这种疾病的治疗目标。本奖学金申请中提出的工作将严格评估一类脂毒性脂质（称为神经酰胺）作为 VLCADD 诱发心力衰竭的驱动因素的作用。越来越多的证据表明，神经酰胺含量升高会导致人类心肌病和心力衰竭和啮齿动物，并且心脏功能随着神经酰胺的消耗而改善。事实上，之前的研究表明 VLCADD 小鼠模型的心脏组织中神经酰胺含量升高。仍然未知神经酰胺积累在 VLCADD 患者发生心力衰竭中起着因果作用。我们的初步数据证实，VLCADD 的体外和体内模型中神经酰胺均升高，体外抑制神经酰胺合成改善了 VLCADD 的许多脂毒性和代谢缺陷，并且体内抑制神经酰胺合成可改善 VLCADD 小鼠模型中的心脏肥大和心脏功能。这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，并且是否有效 VCADD 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估 VLCADD 模型中心力衰竭的特征。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经 Nicola 博士知情同意收集的身份不明的 VLCADD 患者 (IRB_00007551) 的血浆犹他大学 Longo 的临床团队和我们的合作者，犹他大学的 Jerry Vockley 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所起作用的项目在该患者群体中观察到。我们的研究结果将为新颖的应用奠定基础针对 VLCADD 中神经酰胺作为心力衰竭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、技术掌握作为一名追求独立研究事业的年轻科学家的技能和发展。