Mechanisms of Metabolic Dysfunction in Heart Disease

心脏病代谢功能障碍的机制

• 批准号: 7754077
• 负责人: DANIEL A BEARD
• 金额: $ 34.2万
• 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 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7754077
• 关键词: ATP Synthesis Pathway; Accounting; Acetoacetates; Acetyl Coenzyme A; Acute; Affect; Biochemical Pathway; Biological Models; Blood; Brain Hypoxia-Ischemia; Carbohydrates; Cardiac; Cardiomyopathies; Cells; Citric Acid Cycle; Computer Simulation; Data; Data Analyses; Development; Disease; Disease model; Electrophysiology (science); Energy Metabolism; Engineering; Enzymes; Equilibrium; Exercise; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Genetic Models; Glucose; Glycolysis; Goals; Heart; Heart Diseases; Heart failure; Heterogeneity; Hormonal; Hydroxybutyrates; Hypertension; Intervention; Ischemia; Ketone Bodies; Kinetics; Lead; Measurement; Measures; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Muscle Cells; Myocardial; Myocardium; Myopathy; Network-based; Organ; Organelles; Outcome; Oxidative Phosphorylation; Oxygen; PDH kinase; Pathway interactions; Phosphoric Monoester Hydrolases; Physiological; Protocols documentation; Pyruvate; Pyruvates; 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; improved; improved functioning; in vivo; model development; models and simulation; myocardial hypoxia; oxidation; oxygen transport; pressure; reconstitution; research study; respiratory; response; simulation; tool

DESCRIPTION (provided by applicant): 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 energy 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 understand mechanisms leading to reduced capacity to oxidize both fatty acids and carbohydrates, and associated 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 respond 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 bottom-up. Specifically, we will start by obtaining kinetic data to identify the organelle-level model from ex vivo experiments (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 2-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.

描述（由申请人提供）：该提出的项目的重点是确定心脏病中发生的线粒体酶和转运蛋白的分子水平变化如何影响整体心脏功能，并确定如何在分子水平上靶向疗法以改善全体器官水平的功能。拟议的策略是首先根据分离的线粒体悬浮液中的动力学测量值来表征线粒体代谢网络。研究将使用从正常健康心脏和从高血压和心肌病遗传模型获得的心脏获得的线粒体进行。大规模的代谢动力学测量将用于对健康和患病状态的详细代谢模型进行参数化和验证。开发的线粒体模型将集成到心脏能量代谢的细胞水平模型中，并将细胞水平模型分为心脏氧转运的空间分布模拟，从而有效地捕获了心脏氧合中的空间梯度和异质性。所得的组织级模型将用于多种应用：（1）分析健康和患病状态中底物利用的数据，以确定生理控制机制是否以及如何在改变的代谢酶活性和患病心脏中表达的情况下如何失败。这里的目的是了解导致氧化脂肪酸和碳水化合物的能力降低的机制，以及在心脏病中氧化的能量降低。 （2）评估与代谢功能相关的治疗策略的代谢作用。我们将确定该模型是否可以预测几种特定代谢干预措施的作用。这里的目的是为基于工程的方法开发一个强大的平台，以了解和治疗心脏病的代谢作用。这些分析可能会导致识别焦油或改善代谢疗法的策略； （3）评估法规机制对正常和疾病病例中急性缺血和恢复的反应是否不同。要实现这些应用程序，我们必须首先开发一个从自下而上集成的严格模拟平台。具体而言，我们将从离体实验中识别细胞器级模型开始（AIM 1）。在这里，我们建议以响应旨在探测TCA循环和2氧化途径的方案，以获取43个代谢中间体的时间课程动力学数据。这些数据将用于AIM 2用于模型开发，参数化和验证。在AIM 3中追求组织级建模和模拟工具的开发和应用。