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.

项目概要 在本提案中，我们的目标是研究活性氧（ROS）和的综合代谢 能量学，通过实验和计算建模，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”。为了在集成中进行分析 探讨重要疾病中能量和ROS平衡的控制和调节机制 公共卫生方面，我们将研究 2 型糖尿病 (T2DM) 大鼠模型中的工作心肌， 重点关注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，我们试图了解能量和 ROS 通量的相互依赖性，以及 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）对代谢控制的影响。这些研究将应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之后的瞬态分析 稳态机制的扰动。我们计划监测大鼠心脏的代谢变量和 ROS 在力传感器装置的工作条件下装载有荧光指示剂的小梁。这 实验结果将用于约束和微调心肌细胞的计算模型 整合机械、电生理和代谢活动（ECME 模型）。到目前为止，ECME模型 已经能够成功模拟 i) 线粒体膜电位振荡的行为， NADH、谷胱甘肽和 ROS，ii) 线粒体 NADH、钙和 ADP 变化过程中的动态 心脏的供给和需求，以及 iii) 肌膜膜电位的动态变化 发生心律失常的整个心脏中的线粒体振荡。 该模型将扩展到纳入乙酰辅酶A上游途径，即糖酵解、戊糖 磷酸途径和β-氧化。电子传输的更详细的数学描述 呼吸链和 ROS 清除途径的复合体将能够解释 ROS 平衡机制。计算模型将受到代谢控制，以努力 确定参与能量和 ROS 通路网络控制和调节的步骤。 我们坚信，为了对疾病的治疗和预防进行合理的干预， 有关心血管系统的疾病，更深入地了解代谢的综合行为 需要网络。这证明了我们尝试建立一个计算模型的合理性，该模型将导致定量分析 了解心脏生理学的功能失调方面，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。