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Branched chain amino acids in heart failure

支链氨基酸在心力衰竭中的作用

基本信息

批准号：
10371891
负责人：
Zoltan P Arany
金额：
$ 58.31万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10371891
关键词：
ACTA1 gene Address Animal Model Branched-Chain Amino Acids Cardiac Catabolism Cause of Death Cell Culture Techniques Cells Complex Consumption Coronary Data Disease Electrophysiology (science)Evaluation Genes Genetic Health Heart Heart Injuries Heart failure Hospitalization Human In Situ Injury Intervention Investigation Lead Left Ventricular Ejection Fraction Light LoxP-flanked allele Malignant Neoplasms Maps Measures Mediating Metabolic Metabolism Modeling Mus Muscle Myocardium Pathway interactions Patients Pharmacology Phosphotransferases Plasma Play Role Secondary to Skeletal Muscle Slice Testing Therapeutic Tissues Tracer Whole Organism Work adverse outcome cardiogenesis experimental study genetic manipulation heart function hemodynamics improved mortality mouse model novel novel therapeutics oxidation preservation response

项目摘要

SUMMARY Heart failure (HF) is a leading cause of death worldwide, and the leading cause of hospital admissions in patients over 65 in the US. The five-year mortality rate for patients with HF remains ~50%. Neurohormonal blockade has been the mainstay of HF management for decades, but the limits of its benefits have likely been reached. Novel therapies, addressing novel pathways, are direly needed. Mounting evidence indicates that the failing heart is an “engine out of fuel” that fails to use fuel appropriately to satisfy its metabolic demands. Understanding how the heart handles various fuels during health and disease, and finding ways to modulate these pathways, thus holds great promise as novel therapies, orthologous to current neurohormonal blockade. We focus here on branched chain amino acids (BCAAs). Plasma BCAA levels have been noted for decades to be elevated in heart failure, and often to predict adverse outcomes. The expression of BCAA catabolic genes is the most significantly suppressed signature in human failing hearts. Despite these observations, however, the role of BCAAs in heart failure remains poorly understood, and the therapeutic opportunities consequently remain ill-defined. For example, the extent to which BCAA consumption by the heart is required for normal or injured cardiac function is unknown. Similarly unknown is the role of BCAA catabolism in other tissues, in particular the skeletal muscle, which we have shown carries out the lion’s share of BCAA catabolism in the whole organism. Finally, comprehensive quantification of BCAA (and other metabolite) consumption in human hearts, in situ, in both failing and nonfailing conditions, has never been done. To address these questions, we will use here novel genetic murine models;; murine models of various types of heart failure;; and investigations with human cells, tissue, and plasma, to investigate in depth the role of BCAAs in heart failure. These highly focused studies will elucidate the role of BCAA catabolism in cardiac function, with a strong focus on human studies.

摘要：心力衰竭(HF)是世界范围内导致死亡的主要原因之一，也是导致许多患者住院的主要原因。在整个美国，超过65岁的人。患有心力衰竭的患者的未来五年平均死亡率保持在50%左右。神经激素治疗的效果很好。几十年来，它一直是HF的主要管理工具，但它的主要好处的限制很可能一直没有达到。这是一个新奇的问题。除了解决新的心脏途径外，迫切需要治疗方法。越来越多的证据表明，心脏衰竭的主要原因是心脏衰竭。一台“发动机燃料耗尽”的公司未能适当地使用燃料，以满足其主要的新陈代谢需求。在健康和疾病期间，心脏可以处理各种营养物质，并找到方法来进一步调节这些途径，因此。作为一种新颖的药物疗法，一种治疗目前神经激素水平障碍的正畸药物，它有着巨大的前景。我们将在这里重点关注它。支链氨基酸(BCAA)。血浆和BCAA水平几十年来一直没有被注意到，因为它可能会在心脏中升高。失败、失败和失败往往无法预测不良后果。支链氨基酸(BCAA)分解代谢相关基因的表达水平是最显著的。抑制了人类心脏衰竭的标志性变化。然而，尽管有这些观察，但BCAA的主要作用仍然存在于人们的心中。失败仍然没有得到很好的理解，因此治疗失败的机会仍然是不明确的。例如，对于正常的心脏功能或受损的心脏功能，支链氨基酸在多大程度上减少心脏功能的消耗是必需的。它是未知的。同样未知的是支链氨基酸分解代谢在其他组织中的重要作用，特别是在骨骼肌中。我们已经展示并执行了支链氨基酸在整个生物体中分解代谢的第一大份额。最后，。人心脏中支链氨基酸(和其他主要代谢物)的全面定量检测，包括原位检测，以及两者检测。失败和不失败的条件，从来没有被做过。为了更好地解决这些问题，我们将不会在这里使用它。 ;是小鼠的遗传模型；;是小鼠的模型，是各种类型的心力衰竭的模型；DNA检测和研究是对人类干细胞的研究。组织、组织和血浆需要深入调查支气管炎在心力衰竭中的重要作用。这些高度集中的研究将继续。阐明支链氨基酸分解代谢在心脏功能中的重要作用，并将重点放在人类心脏研究上。