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.

项目摘要/摘要非常长链酰基-COA脱氢酶缺乏症（VLCADD）继续引起不屈不挠的心肌。随之而来的心力衰竭和童年死亡。侮辱驱动疾病进度的侮辱，以使能够预防的策略过早死亡。已被视为VLCADD相关病理的驱动力，不可能解释完整的光谱组织缺陷。神经酰胺的积累 - 是VLCADD诱导的心力衰竭和Elucidides潜力的主要贡献者治疗该疾病的治疗目标。一类脂肪毒性脂质物种（称为神经酰胺）是VLCADDD诱导的头部衰竭的驱动因素。越来越多的证据表明，升高的神经酰胺会导致人类心脏病和心力衰竭啮齿动物和CardiACC在神经酰胺耗竭的情况下发挥作用。该神经酰胺在VLCADD小鼠模型中升高。神经酰胺的积累在我们的初步患者的心力衰竭中发挥了因果作用数据证实，在VLCADD的体外和体内模型中，神经酰胺都抑制了神经酰胺的合成改善了VLCADD的许多脂肪毒性和代谢缺陷神经酰胺的合成改善了VLCADD鼠标中的心脏肥大和心脏功能支撑项目将确定神经酰胺是否是VLCADD识别心力衰竭和有效的介体 VLCADD患者的心脏病风险 VLCADD模型中心力衰竭的评估特征的减少或指示。确定血浆神经酰胺是否是VLCADD患者心脏疾病的有效生物标志物使用DE鉴定的VLCADD患者（IRB_00007551）的血浆，并在Nicola博士的知情同意书上收集 Longo在犹他大学的临床团队以及我们的合作者Jerry Vockley博士在大学的临床团队匹兹堡。在这个患者人群中观察到的结果针对神经酰胺的药物策略是VLCADD心力衰竭的关键动力。支撑研究的压缩将极大地丰富申请人的博士前培训，掌握技术技能和发展的年轻科学家从事独立研究职业。