Biosynthetic Pathways in Cardiac Remodeling
心脏重塑中的生物合成途径
基本信息
- 批准号:10220122
- 负责人:
- 金额:$ 74.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-01 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAnabolismAtlasesCarbonCardiacCardiac MyocytesCardiac healthCatabolismCuesDataDeteriorationDilated CardiomyopathyEnzymesEquilibriumExerciseFaceFat BodyFatty acid glycerol estersFunctional disorderGene ExpressionGenesGlucoseGlycolysisGoalsGrowthHeartHeart DiseasesHeart HypertrophyHeart failureHexosaminesHypertrophyInterventionKetone BodiesKetonesKnowledgeMeasuresMetabolicMetabolic PathwayMetabolismMitochondriaMyocardialMyocardial InfarctionNucleic AcidsOrganPathologicPathway interactionsPentosephosphate PathwayPharmacologyPhasePhosphoenolpyruvate CarboxylasePhysiologicalPregnancyProteinsReactionSerineSignal TransductionStimulusStressStructureTestingVentricular Remodelingflexibilitygenetic approachglucose metabolismheart functionheart metabolismimprovedin vivoinnovationinsightmembrane synthesisnoveloxidationpolyolpreferencepressurepreventprogramsresponsestable isotope
项目摘要
The ability of the heart to use multiple substrates provides the flexibility needed to balance catabolic demands
with anabolic requirements; however, the failing heart shifts its energetic reliance toward glucose, and has
diminished fuel flexibility. This switch in fuel use is associated with pathological remodeling, but it remains
unclear how increased reliance on glucose catabolism affects cardiac health. We propose the general
hypothesis that the inability of the failing heart to spare glucose-derived carbon for biosynthetic reactions
causes pathological remodeling. We find that several collateral biosynthetic pathway metabolites are higher in
the compensatory phase of hypertrophy, and that reductions in their abundance coincide with the early stages
of heart failure. Nevertheless, how cardiac metabolic pathways are inter-regulated remains unclear, and how
changes in metabolism elicit myocardial responses to stress remains unanswered. To span such gaps in
knowledge, we will examine how collateral biosynthetic pathways change with cardiac remodeling in vivo by
using deep network stable isotope tracing after pressure overload. We will also examine how physiologic
stimuli for cardiac growth regulate cardiac biosynthetic pathway activity. We will correlate the changes in
biosynthetic pathways with catabolic pathway activity. In Aim 2, we will determine how changes in the cardiac
catabolism modulate collateral biosynthetic pathway activity in the heart. For this, we will force glucose, fat, or
ketone oxidation using pharmacological and genetic approaches and measure glucose carbon fate in anabolic
pathways using deep network stable isotope tracing. Under controlled metabolic conditions, we will construct
an atlas demonstrating how glycolysis, mitochondrial activity, and substrate availability affect glucose carbon
fate and anabolic pathway activity in cardiomyocytes. In Aim 3, we will augment biosynthetic pathway activity
by genetically or allosterically regulating key metabolic steps in the heart or by introducing enzymes to activate
metabolic pathways that are not typically operational in the mammalian heart. We will determine how these
interventions regulate cardiac metabolism and affect myocardial structure and function during pressure
overload-induced heart failure. We will delineate how these interventions affect the metabolism-guided
decisions in cell signaling and gene expression that modulate cardiac hypertrophy and heart failure. Thus, this
project will provide fresh perspectives about how metabolism regulates cardiac health and could identify
innovative metabolic approaches to control cardiac remodeling. In particular, these studies will integrate our
current understanding of cardiac catabolism with new knowledge of how cardiac anabolism is regulated in the
heart. Such insights are conceptually novel and will contribute to understanding how metabolism regulates
cardiac hypertrophy. Thus, these studies will identify: the metabolic pathway flux configurations that occur
during different forms of ventricular remodeling; how fuel selection in the cardiomyocyte regulates anabolic
metabolism; and new metabolic approaches to prevent deleterious remodeling.
心脏使用多个底物的能力提供了平衡分解代谢需求所需的灵活性
有合成代谢要求;但是,失败的心脏将其能量依赖转向葡萄糖,并具有
燃料灵活性降低。这种燃料使用中的转换与病理重塑有关,但仍然存在
尚不清楚对葡萄糖分解代谢的依赖性增加如何影响心脏健康。我们提出了一般
假设失败的心脏无法避免葡萄糖衍生的碳进行生物合成反应
引起病理重塑。我们发现,几种侧外生物合成途径代谢产物较高
肥大的补偿阶段,以及丰度的减少与早期阶段一致
心力衰竭。然而,心脏代谢途径如何相互调节尚不清楚,以及如何
代谢的变化引起对压力的心肌反应,尚未得到解答。跨越这样的差距
知识,我们将研究附带生物合成途径如何随着体内的心脏重塑而变化
压力超负荷后,使用深网稳定的同位素跟踪。我们还将研究生理方式
心脏生长的刺激调节心脏生物合成途径活性。我们将将变化相关联
具有分解代谢途径活性的生物合成途径。在AIM 2中,我们将确定心脏的变化如何
分解代谢调节心脏中的侧支生物合成途径活性。为此,我们将迫使葡萄糖,脂肪或
使用药理和遗传方法的酮氧化并测量合成代谢中的葡萄糖碳命运
使用深网稳定的同位素跟踪的途径。在受控的代谢条件下,我们将构建
一个地图集,证明了糖酵解,线粒体活性和底物的可用性如何影响葡萄糖碳
心肌细胞中的命运和合成代谢途径活性。在AIM 3中,我们将增强生物合成途径活性
通过遗传或变构调节心脏中的关键代谢步骤或引入酶以激活
通常在哺乳动物心脏中运作的代谢途径。我们将确定这些
干预措施调节心脏代谢,并影响压力期间心肌结构和功能
超负荷引起的心力衰竭。我们将描述这些干预措施如何影响新陈代谢引导
细胞信号传导和基因表达的决策调节心脏肥大和心力衰竭。因此,这个
项目将提供有关新陈代谢如何调节心脏健康的新观点,并可以识别
控制心脏重塑的创新代谢方法。特别是,这些研究将整合我们的
对心脏分解代谢的当前了解具有新的了解心脏合成代谢的新知识
心。这种见解在概念上是新颖的,将有助于了解新陈代谢如何调节
心脏肥大。因此,这些研究将识别:发生的代谢途径通量构型
在不同形式的心室重塑中;心肌细胞中的燃料选择如何调节合成代谢
代谢;以及新的代谢方法,以防止有害重塑。
项目成果
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{{ truncateString('Bradford Guy Hill', 18)}}的其他基金
BIOENERGETIC REGULATION OF CARDIAC PROGENITOR CELLS
心脏祖细胞的生物能调节
- 批准号:
8360419 - 财政年份:2011
- 资助金额:
$ 74.98万 - 项目类别:
Project 3 - Regulation of Metabolism by Nitric Oxide
项目 3 - 一氧化氮代谢调节
- 批准号:
8711512 - 财政年份:
- 资助金额:
$ 74.98万 - 项目类别:
Project 3 - Regulation of Metabolism by Nitric Oxide
项目 3 - 一氧化氮代谢调节
- 批准号:
8601974 - 财政年份:
- 资助金额:
$ 74.98万 - 项目类别:
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