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：
Bradford Guy Hill
金额：
$ 74.98万
依托单位：
UNIVERSITY OF LOUISVILLE
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：
https://reporter.nih.gov/project-details/10220122
关键词：
Affect Anabolism Atlases Carbon Cardiac Cardiac Myocytes Cardiac health Catabolism Cues Data Deterioration Dilated Cardiomyopathy Enzymes Equilibrium Exercise Face Fat Body Fatty acid glycerol esters Functional disorder Gene Expression Genes Glucose Glycolysis Goals Growth Heart Heart Diseases Heart Hypertrophy Heart failure Hexosamines Hypertrophy Intervention Ketone Bodies Ketones Knowledge Measures Metabolic Metabolic Pathway Metabolism Mitochondria Myocardial Myocardial Infarction Nucleic Acids Organ Pathologic Pathway interactions Pentosephosphate Pathway Pharmacology Phase Phosphoenolpyruvate Carboxylase Physiological Pregnancy Proteins Reaction Serine Signal Transduction Stimulus Stress Structure Testing Ventricular Remodeling flexibility genetic approach glucose metabolism heart function heart metabolism improved in vivo innovation insight membrane synthesis novel oxidation polyol preference pressure prevent programs response stable 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.

心脏使用多种底物的能力提供了平衡分解代谢需求所需的灵活性具有合成代谢要求；然而，衰竭的心脏将其能量依赖转向葡萄糖，并且已经燃料灵活性降低。燃料使用的这种转变与病理性重塑有关，但它仍然存在目前尚不清楚对葡萄糖分解代谢的依赖增加如何影响心脏健康。我们建议一般假设衰竭的心脏无法将葡萄糖衍生的碳用于生物合成反应引起病理性重塑。我们发现几种侧支生物合成途径代谢物在肥大的代偿阶段，其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仍不清楚，以及如何新陈代谢的变化引起心肌对应激的反应仍然没有答案。为了跨越这样的差距知识，我们将通过体内心脏重塑来研究侧支生物合成途径如何变化压力过载后使用深层网络稳定同位素追踪。我们还将检查生理学如何心脏生长的刺激调节心脏生物合成途径的活性。我们将把这些变化关联起来具有分解代谢途径活性的生物合成途径。在目标 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，我们将强制葡萄糖、脂肪或使用药理学和遗传学方法进行酮氧化并测量合成代谢中的葡萄糖碳命运使用深层网络稳定同位素追踪的途径。在受控的代谢条件下，我们将构建展示糖酵解、线粒体活性和底物可用性如何影响葡萄糖碳的图谱心肌细胞的命运和合成代谢途径活性。在目标 3 中，我们将增强生物合成途径的活性通过遗传或变构调节心脏的关键代谢步骤或通过引入酶来激活哺乳动物心脏中通常不运作的代谢途径。我们将确定如何这些干预措施在压力过程中调节心脏代谢并影响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的调节心脏肥大和心力衰竭的细胞信号传导和基因表达的决定。因此，这个该项目将为新陈代谢如何调节心脏健康提供新的视角，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当前对心脏分解代谢的理解以及心脏合成代谢如何在心脏中进行调节的新知识心。这些见解在概念上是新颖的，将有助于理解新陈代谢如何调节心脏肥大。因此，这些研究将确定：发生的代谢途径通量配置在不同形式的心室重塑过程中；心肌细胞的燃料选择如何调节合成代谢代谢;以及防止有害重塑的新代谢方法。