Integrated Modeling of Cardiac Metabolism and Transport

心脏代谢和运输的综合建模

• 批准号: 7530169
• 负责人: DANIEL A BEARD
• 金额: $ 38.14万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7530169
• 关键词: 5' -AMP-activated protein kinase; 6-Phosphofructo-2-kinase; ATP Hydrolysis; Abbreviations; Accounting; Acetyl-CoA Carboxylase; Acute; Address; Affect; Binding; Biochemical; Biochemical Reaction; Blood flow; Brain Hypoxia-Ischemia; Cardiac; Cardiovascular Diseases; Cardiovascular Models; Carnitine; Cell Respiration; Charge; Chemicals; Chronic; Chronic stress; Citrate; Citrates; Clinical; Computer Simulation; Creatine Kinase; Data; Data Analyses; Diagnosis; Disease; Down-Regulation; Energy Metabolism; Evaluation; Fatty Acids; Free Energy; Fructose; Functional disorder; Funding; Funding Agency; Gene Expression; Glucose; Glycolysis; Goals; Health; Heart; Heart Diseases; Heart failure; Heterogeneity; Homeostasis; Hypertrophic Cardiomyopathy; Image; Intervention; Ions; Ischemia; Ketones; Kinetics; Laboratories; Magnetic Resonance Spectroscopy; Malonyl Coenzyme A; Mechanics; Mediating; Medicine; Metabolic; Metabolic Control; Metabolism; Mining; Mitochondria; Mitochondrial Carnitine Palmitoyltransferase Pathway; Modeling; Myocardial; Myoglobin; Numbers; Operative Surgical Procedures; Oxygen; Pathway interactions; Phosphocreatine; Phosphorylation; Phosphotransferases; Physiological; Play; Process; Property; Protein Dephosphorylation; Proteomics; Public Health; Rate; Rattus; Reaction; Reactive Oxygen Species; Regulation; Research; Role; Series; Simulate; Spectrum Analysis; Staging; Suggestion; System; Technology; Testing; Thermodynamics; Tissues; Transferase; Tricarboxylic Acids; Work; adenylate kinase; base; clinically relevant; fatty acid metabolism; fatty acid oxidation; fatty acid transport; fructose 2,6-diphosphate; glycogen metabolism; heart metabolism; improved; in vivo; inorganic phosphate; ionic balance; long chain fatty acid; oxygen transport; programs; protein phosphatase 2C; pyruvate dehydrogenase; response; simulation; solute; tool; uptake

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.

描述（由申请人提供）：由于代谢特征的改变而导致心脏衰竭，心脏可用于心脏可用的化学能，以ATP水解电位的形式进行工作。实际上，代谢功能障碍可以先于并可能在心脏中发起结构重塑和机械故障中发挥作用。虽然31磷酸酯光谱揭示了心脏病，心力衰竭和肥厚性心肌病的心脏磷酸盐代谢产物特征的显着变化，并且应用了多种代谢靶向疗法以在临床上改善心脏代谢功能，但尚未实现这些技术的全部潜力。这项拟议的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设置中失败，并分析如何基于可用技术观察和操纵心脏能量。我们的方法是开发计算机模型，以模拟心脏组织中的氧气和底物转运，以及细胞内能量代谢，以作为对健康和疾病中能量代谢的调节的定量测试假设。基本的建模框架（根据AIM 1开发）将扩展我们的微血管转运和心脏氧化代谢的集成模型，以说明对原代基质的摄取和处理，以及细胞质和线粒体转运以及相关化合物的代谢。基于关于健康对照和心血管疾病的大鼠模型的代谢通量和浓度的数据，将在AIM 2中对开发的模型进行参数验证和验证。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-COA介导的细胞内脂肪酸转运和柠檬酸盐介导的糖酵解控制控制体内底物代谢的调节。此外，在模型中将提出有关许多知识较低的机制的假设，以测试实验数据。在AIM 3中，我们建议将开发和验证的模型用于一系列临床相关的应用。具体而言，我们将分析有关磁共振光谱得出的磷酸烯酸和氧合的数据，以预测正常和失败的心脏中的代谢状态，并预测非侵入性31p-MRS成像数据可以诊断出心脏中的病理生理代谢状态的敏感性；我们将预测代谢基因表达和底物的可用性如何影响心脏的能量和氧化状态。我们将评估预期治疗心脏病的某些当前和建议的代谢策略如何影响能量代谢。公共卫生相关性的代谢功能障碍在患病的心脏中限制了可以氧化的原发性底物以合成离子稳态和心脏收缩所需的ATP的速率。能量状态减少的潜在后果包括心脏工作和应对急性和慢性应激的能力受损。我们建议开发基于验证的基于仿真的工具，以了解和诊断代谢功能障碍，这些功能障碍可能与能量代谢物的无创成像一起使用。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运作的工具可用于指导旨在调节心脏能量代谢的临床干预措施。