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: 8029925
• 负责人: Sonia del Carmen Cortassa
• 金额: $ 24.6万
• 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 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8029925
• 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; Complex; Computer Simulation; Contracts; Coupling; Dependence; Devices; Diabetes Mellitus; Diffuse; Disease; Electron Transport; Energy Metabolism; Energy Metabolism Pathway; Environment; Enzymes; Equilibrium; Glucose; Glutathione; Glycolysis; 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; Prevention; Process; Production; Public Health; Rattus; Reaction; Reactive Oxygen Species; Reduced Glutathione; Regulation; Respiratory Chain; Signal Transduction; Simulate; Structure; System; Testing; Therapeutic Intervention; Tissues; Titrations; Transducers; Work; base; diabetic; diabetic rat; fatty acid metabolism; fatty acid oxidation; gene therapy; in vivo; inhibitor/antagonist; mitochondrial membrane; oxidation; pyruvate dehydrogenase; respiratory; tool

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Mechanisms of ROS balance and cardiac energy metabolism in Diabetes mellitus Project Narrative Diabetes affects >150 million individuals worldwide and nearly 6% of the US population with a prospective growth to 366 million by 2030. Understanding the function of metabolic networks in diabetes, as proposed herein, is a prerequisite for designing rational therapeutic strategies directed to prevent or manage the disease without producing side effects. The innovative strength of our approach resides in the integrative view of metabolic networks associated with energetic and redox systems in the cell, whose control and regulation is critical for diabetes.

描述（由申请人提供）：在该提案中，我们旨在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“扩散回路控制”，研究活性氧物质（ROS）和能量学的综合代谢。为了以综合的方式分析能量和ROS平衡的控制和调节机制在一个重要的公共卫生疾病，我们将研究工作心肌在2型糖尿病（T2 DM）大鼠模型，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，我们试图了解能量和ROS通量的相互依赖性及其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。这些研究将应用基于抑制剂滴定法的代谢控制分析的最新定量工具，以及稳态方案扰动后的瞬态分析。我们计划监测代谢变量和活性氧在大鼠心脏小梁加载荧光指示剂，在工作条件下的力传感器设备。实验结果将用于约束和微调心肌细胞的计算模型，该模型集成了机械，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以下行为：i）线粒体膜电位、NADH、谷胱甘肽和ROS的振荡，ii）在心脏中的供给和需求变化期间线粒体NADH、钙和ADP的动态，以及iii）在经历心律失常的整个心脏中线粒体振荡期间肌膜电位的动态。 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。呼吸链的电子传递复合物和ROS清除途径的更详细的数学描述，将能够解释ROS平衡的机制。计算模型将受到代谢控制，以确定参与能量和ROS途径网络的控制和调节的步骤。 我们相信，为了对心血管系统疾病的治疗和预防进行合理的干预，需要更深入地了解代谢网络的综合行为。这证明我们试图建立一个计算模型，将导致心脏生理功能障碍方面的定量理解，并指出潜在的目标，可用于治疗干预，无论是药理学，营养或基因治疗。 公共卫生关系：糖尿病影响全球超过1.5亿人，占美国人口的近6%，预计到2030年将增长至3.66亿。如本文所提出的，理解糖尿病中代谢网络的功能是设计旨在预防或管理疾病而不产生副作用的合理治疗策略的先决条件。我们方法的创新优势在于与细胞中的能量和氧化还原系统相关的代谢网络的综合观点，其控制和调节对糖尿病至关重要。