Systems Biology Investigation of Muscle Exercise Metabolism in Diabetes

糖尿病肌肉运动代谢的系统生物学研究

• 批准号: 8111578
• 负责人: Nicola Lai
• 金额: $ 11.87万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-05 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111578
• 关键词: Advisory Committees; Animal Model; Award; Biochemical; Bioenergetics; Biology; Biomedical Engineering; Biopsy; Cell model; Citric Acid Cycle; Complex; Computer Simulation; Control Groups; Cytosol; Data; Data Set; Defect; Diabetes Mellitus; Disease; Drug Formulations; Electron Transport; Energy Metabolism; Energy Transfer; Enzymes; Exercise; Experimental Designs; Fatty Acids; Functional disorder; Future; Glucose; Goals; Health; Impairment; In Vitro; Insulin; Insulin Resistance; Investigation; Kinetics; Knowledge; Lead; Lipids; Measurement; Measures; Membrane Transport Proteins; Mentors; Metabolic; Metabolism; Methodology; Methods; Mitochondria; Modeling; Muscle; Muscle Cells; Muscle Contraction; Muscle Fatigue; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Phosphorylation; Phosphorylation; Physiological; Production; Property; Quality of life; Regulation; Research Personnel; Research Project Grants; Research Training; Science; Skeletal Muscle; Source; Stimulus; System; Systems Biology; Techniques; Testing; Training; Validation; cell growth regulation; data modeling; density; diabetic; diabetic patient; diabetic rat; glucose transport; improved; in vivo; mitochondrial dysfunction; model development; muscle metabolism; oxidation; pyruvate dehydrogenase; research study; response; simulation

DESCRIPTION (provided by applicant): The candidate is a biomedical engineer with expertise in mass transport phenomena and metabolic modeling. His goal is to become an investigator in the field of multi-scale systems biology that combines computational modeling and experimental methods. Through advanced methodology, he will quantify mechanisms relating cellular metabolism to physiological responses in health and state disease. The training award provides a formal framework in which the candidate can gain fundamental knowledge of energy metabolism and muscle biology together with experimental techniques. The proposed plan includes in vitro and in vivo studies as well as related courses in biomedical sciences. The research training emphasizes quantitative understanding of the regulation of cellular energy transfer and metabolism in myocyte and whole skeletal muscle in response to energy demand in control and diabetic rats. Biochemical properties and bioenergetic function of cytosol and mitochondria will be characterized in control and diabetic myocytes. Also, NMR measurements of metabolites within the skeletal muscle will be used to study adaptive changes to different stimuli. The mentored research training has the necessary multi-disciplinary components that include a primary mentor with expertise in mitochondria energetics and a co-mentor with expertise in NMR techniques and metabolism. These mentors will lead an Advisory Committee of investigators with expertise in a) computational modeling of metabolic and physiological systems; b) exercise and insulin resistance in skeletal muscle; c) skeletal muscle fatigue and metabolism. Type 2 diabetes mellitus cause functional adaptations in skeletal muscle in which insulin resistance (IR) is co-expressed by a higher ratio of glycolytic to oxidative capacities. Inadequate coordination between cytosolic and mitochondrial functions may be one mechanism that limits insulin-stimulated glucose utilization. However, the cause-and-effect relationship between mitochondria dysfunction and IR is not defined. This dysfunction may be related to reduced mitochondrial content rather than intrinsic defects or altered metabolic regulation. Possible mechanisms relating amelioration of IR to changes of mitochondria content, mitochondria oxidative function, or membrane transporter function will be evaluated using exercise training. In the proposed plan, the importance of these mechanisms will be evaluated by quantifying the effects of exercise training. The measured responses to muscle contraction or insulin stimulations will include changes in biochemical and biotransport properties as well as bioenergetic functions of the oxidative and glycolytic systems in cytosol and mitochondria. The proposed study combines in vitro and in vivo experiments with mechanistic computational models of skeletal muscle energy metabolism to investigate mechanisms of muscle metabolic dysfunction in diabetes. Simulations with the validated computational models will help to identify hypotheses that can be tested with efficient experimental designs.

描述（由申请人提供）：候选人是一名生物医学工程师，在质量传输现象和代谢建模方面具有专业知识。他的目标是成为多尺度系统生物学领域的研究者，该领域结合了计算建模和实验方法。通过先进的方法，他将量化与健康和疾病状态的生理反应有关的细胞代谢机制。培训奖提供了一个正式的框架，候选人可以获得能量代谢和肌肉生物学的基础知识以及实验技术。拟议的计划包括体外和体内研究以及生物医学科学的相关课程。研究培训强调定量了解对照组和糖尿病大鼠中肌细胞和整个骨骼肌中细胞能量转移和代谢对能量需求的调节。将在对照组和糖尿病患者心肌细胞中表征细胞质和线粒体的生化特性和生物能量功能。此外，骨骼肌内代谢物的NMR测量将用于研究对不同刺激的适应性变化。指导研究培训具有必要的多学科组成部分，包括具有线粒体能量学专业知识的主要导师和具有NMR技术和代谢专业知识的共同导师。这些导师将领导一个咨询委员会的研究人员与专业知识a）代谢和生理系统的计算建模; B）运动和骨骼肌胰岛素抵抗; c）骨骼肌疲劳和代谢。2型糖尿病引起骨骼肌的功能适应，其中胰岛素抵抗（IR）由糖酵解与氧化能力的较高比率共同表达。胞质和线粒体功能之间的不充分协调可能是限制胰岛素刺激的葡萄糖利用的一种机制。然而，线粒体功能障碍和IR之间的因果关系尚未确定。这种功能障碍可能与线粒体含量减少有关，而不是内在缺陷或代谢调节改变。将使用运动训练评估与改善IR相关的线粒体含量、线粒体氧化功能或膜转运蛋白功能的变化的可能机制。在拟议的计划中，将通过量化运动训练的效果来评估这些机制的重要性。所测量的对肌肉收缩或胰岛素刺激的反应将包括细胞质和线粒体中的氧化和糖酵解系统的生物化学和生物转运特性以及生物能功能的变化。该研究结合了体外和体内实验与骨骼肌能量代谢的机械计算模型，以研究糖尿病肌肉代谢功能障碍的机制。使用经过验证的计算模型进行模拟将有助于确定可以通过有效的实验设计进行测试的假设。