Metabolic Reprogramming and Pulmonary Vascular Disease in Congenital Heart Disease

计划摘要 肺血管疾病(PVD)可能是先天性心脏病儿童最重要的并发症 导致肺血流量(PBF)和压力增加的疾病(CHD)。出生后，出现了 脑室(例如室间隔缺损)或大血管(例如室干)的大交通 动脉硬化)使肺循环暴露在血流和压力异常升高的情况下，从而导致 进行性肺血管结构和功能异常。新陈代谢重新编程 越来越被认为是早期肺血管损伤和疾病的关键组成部分。血管 我们的分流羔羊模型的形态学研究显示分流术后肺小动脉增加了2倍 与对照羔羊相比。这与人类的动脉计数减少是相反的 晚期疾病。这种早期血管生成的增加可能代表了对血流增加的适应 和压力。为此，发展一种高增殖、抗凋亡的内皮细胞表型是必要的。 血管生成反应。此外，它需要戏剧性的新陈代谢重新编程来供应这些细胞 细胞分裂所需的必要的生物合成前体，同时减少细胞 由于消耗增加和呼吸减少而导致的ATP水平。我们已经将这种三磷酸腺苷的下降与 热休克蛋白90介导的NO信号丢失与内皮功能障碍和血管病变的发展 改建。因此，这一PPG集中在增加我们对以下方面的理解：i)不同的影响 对细胞代谢编程的机械力；ii)影响翻译后修饰(PTM) 参与代谢重编程的关键信号通路；iii)线粒体网络之间的相互作用 动力学、新陈代谢和细胞存活；iv)这些途径如何相互作用以破坏HSP90介导的NO 信号转导；以及v)治疗PBF增加的CHD的新治疗策略。关键的新途径是 通过我们对新陈代谢的深入调查，确定了每个项目的重点 重新编程是肺血管疾病发展的基础，并根据其能力进行选择 促进与谷氨酰胺分解和有氧糖酵解相关的细胞反应谱(项目1)， 细胞氧化和线粒体生物能量学(项目2)，线粒体网络动力学和 有丝分裂(项目3)、细胞增殖和凋亡(项目1和项目3)。调查是综合的 通过我们的三个PPG项目，以充分了解代谢重新编程如何导致HSP90的丢失- 介导了NO信号，并代表了这一PPG的主题基础。协同效应源于 个别项目和科学核心之间的互动，以及我们的方案方法，将促进 加深对机械力如何改变细胞代谢、NO信号和内皮的理解 功能，以及新的个体化治疗方法的发展，以减轻肺血管疾病 先天患有先天性心脏病的儿童，会导致PBF和压力增加。

PROGRAM SUMMARY Pulmonary vascular disease (PVD) is perhaps the most important complication for children with congenital heart disease (CHD) that results in increased pulmonary blood flow (PBF) and pressure. Postnatally, the presence of large communications at the level of the ventricles (e.g. ventricular septal defect) or great vessels (e.g. truncus arteriosus) exposes the pulmonary circulation to abnormal elevations in blood flow and pressure, which results in progressive structural and functional abnormalities of the pulmonary vasculature. Metabolic reprogramming is increasingly recognized as a critical component of early pulmonary vascular injury and disease. Vascular morphology studies in our Shunt lamb model demonstrate a >2-fold increase in pulmonary arterioles in Shunt compared to control lambs. This is opposed to the decrease in arterial counts demonstrated in humans with advanced disease. This early increase in angiogenesis likely represents an adaptation to the increase in flow and pressure. The development of a hyperproliferative, anti-apoptotic endothelial phenotype is necessary for this angiogenic response. Further, it requires a dramatic metabolic reprogramming that serves to supply these cells with the necessary biosynthetic precursors required for cell division while simultaneously decreasing cellular ATP levels due to increased consumption and decreased respiration. We have linked this decrease in ATP to the loss of hsp90-mediated NO signaling and the development of endothelial dysfunction and vascular remodeling. Thus, this PPG intensely focuses on increasing our understanding of: i) the differential effects of mechanical forces on cellular metabolic programming; ii) post translational modifications (PTMs) that influence key signaling pathways involved in metabolic reprogramming; iii) interactions between mitochondrial network dynamics, metabolism, and cellular survival; iv) how these pathways interact to disrupt hsp90-mediated NO signaling; and v) novel therapeutic strategies for treating CHD with increased PBF. The key novel pathways that comprise the focus of each Project were identified by our intensive investigations into the metabolic reprogramming underlying the development of pulmonary vascular disease and selected for their capacity to contribute to a spectrum of cellular responses related to glutaminolysis and aerobic glycolysis (Project #1), cellular ß-oxidation and mitochondrial bioenergetics (Project #2), mitochondrial network dynamics and mitophagy (Project #3), and cell proliferation and apoptosis (Projects #1 & #3). Investigations are integrated across our three PPG projects to fully understand how metabolic reprogramming leads to the loss of hsp90- mediated NO signaling and represents the thematic underpinning of this PPG. The synergy derived from the interactions between individual Projects and scientific Cores, with our programmatic approaches, will promote an increased understanding of how mechanical forces modify cell metabolism, NO signaling and endothelial function, and the development of novel, individualized therapies to attenuate pulmonary vascular disease in children born with CHD that result in increased PBF and pressure.