Mechanisms of Metabolic Dysfunction in Heart Disease

心脏病代谢功能障碍的机制

• 批准号: 8208180
• 负责人: DANIEL A BEARD
• 金额: $ 32.36万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8208180
• 关键词: ATP Synthesis Pathway; Accounting; Acetoacetates; Acetyl Coenzyme A; Acute; Affect; Alzheimer' s Disease; Biochemical Pathway; Biological Models; Blood; Brain Hypoxia-Ischemia; Carbohydrates; Cardiac; Cardiomyopathies; Cells; Citric Acid Cycle; Clinical; Computer Simulation; Data; Data Analyses; Development; Diabetes Mellitus; Disease; Disease model; Electrophysiology (science); Energy Metabolism; Engineering; Enzyme Kinetics; Enzymes; Equilibrium; Exercise; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Genetic Models; Glucose; Glycolysis; Goals; Heart; Heart Diseases; Heart failure; Heterogeneity; High Pressure Liquid Chromatography; Homeostasis; Hormonal; Hydroxybutyrates; Hypertension; Intervention; Ischemia; Ketone Bodies; Kinetics; Lead; Malignant Neoplasms; Measurement; Measures; Metabolic; Metabolic Control; Metabolism; Mitochondria; Modeling; Molecular; Muscle Cells; Myocardial; Myocardium; Myopathy; Network-based; Organ; Organelles; Outcome; Oxidative Phosphorylation; Oxygen; PDH kinase; Parkinson Disease; Pathway interactions; Phosphoric Monoester Hydrolases; Physiological; Protocols documentation; Public Health; Pyruvate; Rattus; Recovery; Source; Starvation; Stress; Suspension substance; Suspensions; System; Tars; Therapeutic; Therapeutic Effect; Time; Tissues; Translating; Validation; Work; base; case control; dehydrogenation; design; enzyme activity; fatty acid oxidation; fatty acid transport; flexibility; glycogenolysis; human disease; improved; improved functioning; in vivo; mitochondrial dysfunction; model development; models and simulation; myocardial hypoxia; operation; oxidation; oxygen transport; pressure; reconstitution; research study; respiratory; response; simulation; tool

Project Summary This proposed project is focused on determining how molecular-level changes in mitochondrial enzymes and transporters that occur in heart disease affect overall cardiac function and determining how therapies may be targeted at the molecular level to improve function at the whole-organ level. The proposed strategy is to first characterize the mitochondrial metabolic network based on quenched kinetic measurements in suspensions of isolated mitochondria. Studies will be carried out using mitochondria obtained from both normal healthy hearts and hearts obtained from a genetic model of hypertension and cardiomyopathy. Large-scale metabolic kinetic measurements will be used to parameterize and validate detailed metabolic models for both the healthy and diseased states. The developed mitochondrial models will be integrated into cell-level models of cardiac en- ergy metabolism, and the cell-level models into a spatially distributed simulation of cardiac oxygen transport that effectively captures spatial gradients and heterogeneity in oxygenation of the myocardium. The resulting tissue-level model will be used for a number of applications: (1) to analyze data on substrate utilization in healthy and diseased states to determine if and how physiological control mechanisms fail in the setting of altered metabolic enzyme activity and expression in the diseased heart. The aim here will be to un- derstand mechanisms leading to reduced capacity to oxidize both fatty acids and carbohydrates, and associ- ated reduction in energetic state, in heart disease; (2) to evaluate metabolic effects of therapeutic strategies tied to metabolic function. We will determine if the model can predict the action of several specific metabolic interventions. The aim here is to develop a powerful platform for an engineering-based approach to under- standing and treating the metabolic effects of heart disease. These analyses may lead to identification of tar- gets or strategies for improving metabolic therapy; and (3) to evaluate if and how regulatory mechanisms re- spond differently to acute ischemia and recovery in the normal and disease cases. To realize these applications, we must first develop a rigorous simulation platform, integrated from the bot- tom-up. Specifically, we will start by obtaining kinetic data to identify the organelle-level model from ex vivo ex- periments (Aim 1). Here we propose to obtain (and make available) time-course kinetic data on 43 metabolic intermediates in response to protocols designed to probe the TCA cycle and ¿-oxidation pathways. These data will be used in Aim 2 for model development, parameterization, and validation. Development and application of tissue-level modeling and simulation tools are pursued in Aim 3. Project Relevance to Public Health Mitochondrial dysfunction is implicated in many human diseases including cancer, Alzheimer's disease, Park- inson's disease, and heart disease. 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. We propose to obtain large-scale kinetic data on cardiac cellular energetics and to use those data to develop vali- dated simulation-based tools to understand metabolic dysfunction in heart disease. 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.

项目摘要 该提出的项目的重点是确定分子水平如何变化线粒体酶和 心脏病中发生的转运蛋白会影响整体心脏功能并确定疗法的可能如何 针对分子水平以提高整个器官水平的功能。拟议的策略是首先 表征基于淬火的动力学测量值的线粒体代谢网络 孤立的线粒体。研究将使用从两个正常健康心脏获得的线粒体进行 心脏从高血压和心肌病的遗传模型中获得。大规模代谢动力学 测量将用于对健康和 病态。已开发的线粒体模型将集成到心脏电源的细胞级模型中 ERGY代谢，将细胞级模型纳入心脏氧运输的空间分布的模拟 这有效地捕获了心肌氧合中的空间梯度和异质性。 生成的组织级模型将用于多种应用：（1）分析基板数据 在健康和解散状态中利用以确定物理控制机制是否以及如何失败 设置改变的代谢酶活性和在解散心脏中的表达。这里的目的是不 施加机制导致氧化脂肪酸和碳含氧化物的能力降低，缔合 降低能量状态，心脏病； （2）评估治疗策略的代谢作用 与代谢功能有关。我们将确定该模型是否可以预测几种特定代谢的作用 干预措施。这里的目的是为基于工程的方法开发一个强大的平台 站立和治疗心脏病的代谢作用。这些分析可能导致焦虑的鉴定 获得改善代谢疗法的策略； （3）评估监管机制是否以及如何重新 在正常和疾病病例中，赞助商与急性缺血和恢复不同。 要实现这些应用程序，我们必须首先开发一个严格的仿真平台，该平台是根据机器人集成的 特别是，我们将首先获得动力学数据，以确定从离体外的细胞器级模型 肉食（目标1）。在这里，我们建议获得（并提供）有关43代谢的时间课程动力学数据 响应于旨在探测TCA循环和 - 氧化途径的方案的响应。这些数据 将用于AIM 2进行模型开发，参数化和验证。开发和应用 在AIM 3中追求组织级建模和仿真工具。项目与公共卫生的相关性 线粒体功能障碍在许多人类疾病中实施，包括癌症，阿尔茨海默氏病，公园 - Inson病和心脏病。解散心脏的代谢功能障碍限制了主要的速度 可以将底物氧化以合成离子稳态和心脏收缩所需的ATP。我们 提议获得有关心脏细胞能量的大规模动力学数据，并使用这些数据来发展vali- 基于模拟的日期工具了解心脏病中的代谢功能障碍。此外，我们的建议 模拟心脏病中代谢控制机制的病理生理运作的工具可能 用于指导旨在调节心脏能量代谢的临床干预措施。