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:10599927
- 负责人:
- 金额:$ 58.31万
- 依托单位:
- 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 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:ACTA1 geneAddressBranched-Chain Amino AcidsCardiacCatabolismCause of DeathCell Culture TechniquesCellsComplexConsumptionCoronaryDataDevelopmentDiseaseElectrophysiology (science)EvaluationGenesGeneticHealthHeartHeart InjuriesHeart failureHospitalizationHumanIn SituInjuryInterventionInvestigationIschemiaLeft Ventricular Ejection FractionLightLoxP-flanked alleleMalignant NeoplasmsMapsMeasuresMediatingMetabolicMetabolismModelingMusMuscleMyocardiumPathway interactionsPatientsPhosphotransferasesPlasmaPlayRoleSecondary toSkeletal MuscleSliceTestingTherapeuticTissuesTracerWhole OrganismWorkadverse outcomeexperimental studygenetic manipulationheart functionhemodynamicsimprovedmodel organismmortalitymouse modelnovelnovel therapeuticsoxidationpharmacologicpreservationresponse
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.
总结
心力衰竭(HF)是全球死亡的主要原因,也是患者住院的主要原因
在美国,65岁以上的人死亡。HF患者的5年死亡率仍为~ 50%。神经激素阻滞剂
几十年来,它一直是HF管理的支柱,但其益处可能已经达到极限。
迫切需要新的治疗途径。越来越多的证据表明,衰竭的心脏
一个“发动机的燃料”,未能适当地使用燃料,以满足其代谢的需求。了解如何
心脏在健康和疾病期间处理各种燃料,并找到调节这些途径的方法,
作为一种新的治疗方法,具有很大的前景,可以替代目前的神经激素阻滞。我们在这里关注
支链氨基酸(BCAA)。几十年来,血浆BCAA水平已被注意到在心脏中升高,
BCAA分解代谢基因的表达是最显著的,
然而,尽管有这些观察结果,BCAAs在心脏衰竭中的作用仍然存在。
失败仍然知之甚少,因此治疗机会仍然不明确。
例如,心脏消耗BCAA的程度是正常或受损的心脏功能所需的
同样未知的是支链氨基酸催化剂在其他组织中的作用,特别是骨骼肌,
我们已经证明,它在整个生物体中承担了最大份额的BCAA催化剂。最后,
全面量化人体心脏中BCAA(和其他代谢物)的原位消耗量,无论是在
失败和非失败的条件,从来没有做过。为了解决这些问题,我们将在这里使用新的
遗传鼠模型;各种类型心力衰竭的非特异性鼠模型;使用人细胞的研究和调查,
组织和血浆,深入研究支链氨基酸在心力衰竭中的作用。这些高度集中的研究将
阐明BCAA催化剂在心脏功能中的作用,重点关注人类研究。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The newborn heart GLAdly benefits from maternal milk.
新生儿心脏很高兴地受益于母乳。
- DOI:10.20517/jca.2023.25
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Bowman,CaitlynE;Arany,Zoltan
- 通讯作者:Arany,Zoltan
Integrated landscape of cardiac metabolism in end-stage human nonischemic dilated cardiomyopathy.
- DOI:10.1038/s44161-022-00117-6
- 发表时间:2022-09
- 期刊:
- 影响因子:0
- 作者:Flam, Emily;Jang, Cholsoon;Murashige, Danielle;Yang, Yifan;Morley, Michael P;Jung, Sunhee;Kantner, Daniel S;Pepper, Hannah;Bedi, Kenneth C Jr;Brandimarto, Jeff;Prosser, Benjamin L;Cappola, Thomas;Snyder, Nathaniel W;Rabinowitz, Joshua D;Margulies, Kenneth B;Arany, Zolt
- 通讯作者:Arany, Zolt
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Zoltan P Arany其他文献
Zoltan P Arany的其他文献
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{{ truncateString('Zoltan P Arany', 18)}}的其他基金
Comprehensive quantification of fuel use in cold-induced thermogenesis in vivo
体内冷诱导生热过程中燃料使用的综合量化
- 批准号:
10637680 - 财政年份:2023
- 资助金额:
$ 58.31万 - 项目类别:
High-throughput screening for modulators of vascular fat transport to treat and prevent diabetes
高通量筛选血管脂肪转运调节剂以治疗和预防糖尿病
- 批准号:
10343859 - 财政年份:2021
- 资助金额:
$ 58.31万 - 项目类别:
High-throughput screening for modulators of vascular fat transport to treat and prevent diabetes
高通量筛选血管脂肪转运调节剂以治疗和预防糖尿病
- 批准号:
10331230 - 财政年份:2021
- 资助金额:
$ 58.31万 - 项目类别:
Keeping fat out of muscle - Role of Branched Amino Acids
保持肌肉中的脂肪——支链氨基酸的作用
- 批准号:
10186735 - 财政年份:2018
- 资助金额:
$ 58.31万 - 项目类别:
Keeping fat out of muscle - Role of Branched Amino AcidsAmino Acids in Insulin Resistance
保持肌肉中的脂肪 - 支链氨基酸氨基酸在胰岛素抵抗中的作用
- 批准号:
10736605 - 财政年份:2018
- 资助金额:
$ 58.31万 - 项目类别:
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