Integrated Modeling of Cardiac Metabolism and Transport

描述（由申请人提供）：由于代谢特征改变，心力衰竭时心脏做功的化学能（以ATP水解电位的形式）减少。事实上，代谢功能障碍可以先于心脏结构重塑和机械功能障碍，并可能在心脏结构重塑和机械功能障碍中发挥作用。虽然31磷酸盐光谱揭示了心脏病、心力衰竭和肥厚性心肌病中心脏磷酸盐代谢谱的显著变化，并且各种代谢靶向疗法被应用于临床以改善心脏代谢功能，但这些技术的全部潜力尚未实现。这项拟议研究的总体目标是应用心脏组织计算机建模工具来量化控制工作心脏中代谢通量的生理机制，以确定这些机制如何在各种病理生理学设置中失败，并分析如何根据现有技术观察和操纵心脏能量学。我们的方法是开发计算机模型，模拟心脏组织和细胞内能量代谢的氧气和底物运输，作为定量检验的假设，在健康和疾病的能量代谢的调节。基本建模框架（根据目标1开发）将扩展我们的微血管运输和心脏氧化代谢的综合模型，以解释主要底物的摄取和处理以及相关化合物的细胞质和线粒体运输和代谢。开发的模型将在目标2中基于健康对照和心血管疾病大鼠模型的代谢通量和浓度数据进行参数化和验证。基于这些数据，我们将评估已建立的生理控制机制的作用，包括丙二酰辅酶A介导的调节细胞内脂肪酸转运和柠檬酸盐介导的糖酵解调节在控制体内底物代谢。此外，关于一些知之甚少的机制的假设将在模型中制定，以测试对实验数据。在目标3中，我们建议将开发和验证的模型用于一系列临床相关应用。具体来说，我们将分析来自磁共振波谱的磷酸能学和氧合数据，以预测正常和衰竭心脏的代谢状态，并预测非侵入性31 P-MRS成像数据诊断心脏病理生理代谢状态的灵敏度;我们将预测代谢基因表达和底物可用性的慢性变化如何影响心脏的能量和氧化状态;并且我们将评估某些当前和提议的用于治疗心脏病的代谢策略预期如何影响能量代谢。公共卫生相关性病变心脏的代谢功能障碍限制了主要底物被氧化以合成离子稳态和心脏收缩所必需的ATP的速率。能量状态减弱的潜在后果包括心脏工作能力受损以及对急性和慢性压力的反应。我们建议开发经验证的基于模拟的工具，以了解和诊断代谢功能障碍，可用于与能量代谢物的无创成像。此外，我们提出的用于模拟心脏病中代谢控制机制的病理生理学操作的工具可用于指导旨在调节心脏能量代谢的临床干预。

DESCRIPTION (provided by applicant): Chemical energy available for the heart to do work, in the form of the ATP hydrolysis potential, is diminished in heart failure as a result of an altered metabolic profile. In fact, metabolic dysfunction can precede and may play a role in initiating structural remodeling and mechanical malfunction in the heart. While 31phosphate spectroscopy reveals significant changes in the cardiac phosphate metabolite profile in heart disease, heart failure, and hypertrophic cardiomyopathy, and a variety of metabolically targeted therapies are applied to improve cardiac metabolic function clinically, the full potential of these technologies have not been realized. The overall goals of this proposed study are to apply cardiac tissue computer modeling tools to quantify the physiological mechanisms controlling metabolic fluxes in the working heart, to determine how these mechanisms fail in a variety of pathophysiological settings, and to analyze how cardiac energetics may be observed and manipulated based on available technology. Our approach is to develop computer models that simulate oxygen and substrate transport in cardiac tissue and intracellular energy metabolism to serve as quantitatively testable hypotheses regarding the regulation of energy metabolism in health and disease. The basic modeling framework (developed under Aim 1) will extend our integrated model of microvascular transport and cardiac oxidative metabolism to account for uptake and handling of primary substrates and cytoplasmic and mitochondrial transport and metabolism of related compounds. The developed models will be parameterized and validated in Aim 2 based on data on metabolic fluxes and concentrations from healthy controls and rat models of cardiovascular disease. Based on these data, we will evaluate the roles of established physiological control mechanisms-including malonyl-CoA-mediated regulation of intracellular fatty acid transport and citrate-mediated regulation of glycolysis-in controlling in vivo substrate metabolism. In addition, hypotheses regarding a number of poorly understood mechanisms will be formulated in the model to test against experimental data. In Aim 3 we propose to use the developed and validated models for a series of clinically relevant applications. Specifically, we will analyze data on phosphoenergetics and oxygenation derived from magnetic resonance spectroscopy to predict the metabolic state in normal and failing hearts and predict the sensitivity at which noninvasive 31P-MRS imaging data can diagnose a pathophysiological metabolic state in the heart; we will predict how chronic shifts in metabolic gene expression and substrate availability impact the energetic and oxidative state of the heart; and we will evaluate how certain current and proposed metabolic strategies for treatment of heart disease are expected to affect energy metabolism. PUBLIC HEALTH RELEVANCE Metabolic dysfunction in the diseased heart limits the rate at which primary substrates can be oxidized to synthesize ATP necessary for ionic homeostasis and cardiac contraction. The potential consequences of a diminished energetic state include an impaired the ability of the heart to work and respond to acute and chronic stresses. We propose to develop validated simulation-based tools to understand and diagnosis of metabolic dysfunction that may be used in concert with noninvasive imaging of energy metabolites. In addition, our proposed tools for simulation of the pathophysiological operation of metabolic control mechanisms in heart disease may be used to guide clinical interventions aimed at modulation of cardiac energy metabolism.