Biosynthetic Pathways in Cardiac 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 然而，衰竭的心脏将其能量依赖转移到葡萄糖上， 降低燃料灵活性。这种燃料使用的转换与病理性重塑有关，但它仍然存在。 尚不清楚增加对葡萄糖催化剂的依赖如何影响心脏健康。我们建议将军 假设衰竭的心脏无法为生物合成反应保留葡萄糖衍生的碳， 导致病理性重塑我们发现，几种侧支生物合成途径代谢物在 肥大补偿阶段和它们的丰度的减少与早期阶段一致 心脏衰竭的症状然而，心脏代谢途径如何相互调节仍不清楚， 代谢的变化引起心肌对应激的反应仍然没有答案。跨越这样的差距， 知识，我们将研究如何侧支生物合成途径的变化与心脏重塑在体内， 采用压力过载后的深网稳定同位素示踪。我们还将研究如何生理 心脏生长刺激调节心脏生物合成途径活性。我们将把这些变化 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 钙调素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以及测量合成代谢中葡萄糖碳命运 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 说明糖酵解、线粒体活性和底物可用性如何影响葡萄糖碳的图谱 心肌细胞中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中的关键代谢步骤，或通过引入酶来激活 在哺乳动物心脏中通常不起作用的代谢途径。我们将确定这些 干预调节心脏代谢并影响压力期间的心肌结构和功能 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代谢指导的 细胞信号传导和基因表达的决定，调节心脏肥大和心力衰竭。因此， 该项目将提供关于新陈代谢如何调节心脏健康的新观点，并可以识别 创新的代谢方法来控制心脏重塑。特别是，这些研究将整合我们的 目前对心脏激动剂的理解，以及对心脏激动剂如何在心脏中调节的新知识， 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期间;心肌细胞中的燃料选择如何调节合成代谢 代谢;和新的代谢方法，以防止有害的重塑。

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.