Mechanisms of ROS Balance and Cardiac Energy Metabolism in Diabetes Mellitus

糖尿病中ROS平衡与心脏能量代谢的机制

• 批准号: 8204907
• 负责人: Sonia del Carmen Cortassa
• 金额: $ 20.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-15 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204907
• 关键词: Accounting; Acetyl Coenzyme A; Address; Adenine Nucleotides; Adverse effects; Affect; Animals; Arrhythmia; Behavior; Biochemical Pathway; Calcium; Carbohydrates; Cardiac; Cardiac Myocytes; Cardiovascular system; Cells; Complex; Computer Simulation; Contracts; Coupling; Dependence; Devices; Diabetes Mellitus; Diffuse; Disease; Electron Transport; Energy Metabolism; Energy Metabolism Pathway; Environment; Enzymes; Equilibrium; Glucose; Glutathione; Glycolysis; Growth; Heart; Hyperglycemia; Individual; Insulin; Intervention; Lead; Mechanics; Membrane Potentials; Metabolic; Metabolic Control; Metabolic Pathway; Metabolism; Metformin; Methods; Mitochondria; Modeling; Monitor; Muscle; Myocardium; NADH; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Output; Oxidation-Reduction; Pathway interactions; Pentosephosphate Pathway; Pharmaceutical Preparations; Phosphorylation; Physiological; Physiology; Population; Prevention; Process; Production; Public Health; Rattus; Reaction; Reactive Oxygen Species; Reduced Glutathione; Regulation; Respiratory Chain; Signal Transduction; Simulate; Structure; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; Titrations; Transducers; Work; base; design; diabetic; diabetic rat; fatty acid metabolism; fatty acid oxidation; gene therapy; in vivo; inhibitor/antagonist; innovation; mitochondrial membrane; oxidation; prevent; prospective; pyruvate dehydrogenase; respiratory; tool

Project Summary In this proposal we aim to study the integrated metabolism of reactive oxygen species (ROS) and energetics, experimentally and by computational modeling, applying two recently introduced concepts: "Redox- optimized ROS balance" (R-OR balance), and "control by diffuse loops". In order to analyze in an integrated manner the mechanisms of control and regulation of energy and ROS balance in an important disease for public health, we will investigate working cardiac muscle in a type 2 diabetes mellitus (T2DM) rat model, focusing on the effects of insulin and metformin upon energy and ROS pathways. In the diabetic cardiac muscle, we seek to understand the interdependence of energy and ROS fluxes and their relation to the redox environment, We will focus on the effects of insulin and metformin (a widely-used anti-hyperglycemic drug) on metabolic control. These studies will apply state of the art quantitative tools of metabolic control analysis based on the inhibitor titration method, and on the analysis of transients after perturbation of the steady state regime. We plan to monitor metabolic variables and ROS in rat cardiac trabeculae loaded with fluorescent indicators, under working conditions in a force transducer device. The experimental results will be used to constrain and fine-tune a computational model of the cardiac myocyte that integrates mechanical, electrophysiological and metabolic activities (ECME model). So far, the ECME model has been able to successfully simulate the behavior of i) oscillations in mitochondrial membrane potential, NADH, glutathione, and ROS, ii) the dynamics of mitochondrial NADH, calcium, and ADP during changes in supply and demand in the heart, and iii) the dynamics of the sarcolemmal membrane potential during mitochondrial oscillations in whole hearts undergoing arrhythmias. The model will be extended to incorporate pathways upstream Acetyl CoA, namely glycolysis, pentose phosphate pathways and beta-oxidation. A more detailed mathematical description of the electron-transport complexes of the respiratory chain, and of the ROS scavenging pathways, will enable accounting for the mechanisms of ROS balance. The computational model will be subjected to metabolic control in an effort to identify the steps that participate in the control and regulation of the network of energy and ROS pathways. We are convinced that in order to perform a rational intervention in the treatment and prevention of a disease regarding the cardiovascular system, a deeper understanding of the integrated behavior of metabolic networks is needed. This justifies our attempt to build a computational model that will lead to a quantitative understanding of the dysfunctional aspects of heart physiology, and point out potential targets that could be used for therapeutic interventions, either pharmacological, nutritional or by gene therapy.

项目摘要 在这个提议中，我们的目标是研究活性氧（ROS）的综合代谢， 能量学，实验和计算建模，应用两个最近引入的概念：“氧化还原- 优化的ROS平衡”（R-OR平衡）和“通过扩散环控制”。为了分析在一个综合的 的方式控制和调节能量和活性氧平衡的机制，在一个重要的疾病， 公共卫生，我们将研究2型糖尿病（T2 DM）大鼠模型中的工作心肌， 重点是胰岛素和二甲双胍对能量和ROS途径的影响。 在糖尿病心肌中，我们寻求了解能量和活性氧通量的相互依赖性， 它们与氧化还原环境的关系，我们将重点关注胰岛素和二甲双胍（一种广泛使用的 抗高血糖药物）对代谢控制的作用。这些研究将采用最先进的定量工具， 基于抑制剂滴定法的代谢控制分析，以及 稳定状态的扰动。我们计划监测大鼠心脏中的代谢变量和ROS， 在力传感器装置中的工作条件下，装载有荧光指示剂的小梁。的 实验结果将用于约束和微调心肌细胞的计算模型， 集成了机械、电生理和代谢活动（ECME模型）。到目前为止，ECME模型 已经能够成功地模拟i）线粒体膜电位的振荡， ii）线粒体NADH、钙和ADP在细胞内的变化过程中的动力学， 心脏中的供应和需求，以及iii）在心脏中的心肌细胞膜电位的动态变化。 线粒体振荡在整个心脏经历心律失常。 该模型将被扩展到纳入上游途径乙酰辅酶A，即糖酵解，戊糖 磷酸途径和β-氧化。电子输运的更详细的数学描述 呼吸链和ROS清除途径的复合物将能够解释 ROS平衡机制。计算模型将受到代谢控制， 确定参与能量和ROS途径网络的控制和调节的步骤。 我们相信，为了在治疗和预防中进行合理的干预， 关于心血管系统的疾病，更深入地了解代谢的综合行为， 网络是必要的。这证明我们试图建立一个计算模型，将导致一个定量的 了解心脏生理学的功能障碍方面，并指出可能的潜在目标， 用于药物、营养或基因治疗的治疗干预。