Systems Biology Investigation of Muscle Exercise Metabolism in Diabetes

应聘者描述(由申请者提供)：应聘者为生物医学工程师，具有物质传输现象和代谢模型方面的专业知识。他的目标是成为一名结合计算建模和实验方法的多尺度系统生物学领域的研究人员。通过先进的方法论，他将量化与健康和疾病状态下的生理反应有关的细胞代谢机制。训练奖提供了一个正式的框架，候选人可以在其中获得能量代谢和肌肉生物学的基本知识以及实验技术。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。研究性训练强调定量了解肌细胞和整个骨骼肌中细胞能量转移和代谢的调节，以响应对照组和糖尿病大鼠的能量需求。对照和糖尿病心肌细胞的胞浆和线粒体的生化特性和生物能量功能将被描述。此外，骨骼肌内代谢物的核磁共振测量将用于研究对不同刺激的适应性变化。指导研究培训有必要的多学科组成部分，其中包括一名具有线粒体能量学专业知识的主要导师和一名具有核磁共振技术和新陈代谢专业知识的联合导师。这些导师将领导一个由研究人员组成的咨询委员会，他们的专长是a)代谢和生理系统的计算建模；b)骨骼肌中的运动和胰岛素抵抗；c)骨骼肌疲劳和新陈代谢。2型糖尿病引起骨骼肌的功能适应，其中胰岛素抵抗(IR)与糖酵解与氧化能力的高比率共同表现。胞浆和线粒体功能之间的不协调可能是限制胰岛素刺激的葡萄糖利用的机制之一。然而，线粒体功能障碍与IR之间的因果关系尚未明确。这种功能障碍可能与线粒体含量减少有关，而不是与固有缺陷或代谢调节改变有关。IR改善的可能机制与线粒体含量、线粒体氧化功能或膜转运蛋白功能的变化有关，将通过运动训练进行评估。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。对肌肉收缩或胰岛素刺激的测量反应将包括生化和生物运输特性的变化，以及胞浆和线粒体中氧化和糖酵解系统的生物能量功能的变化。这项拟议的研究将体外和体内实验与骨骼肌能量代谢的机械计算模型相结合，以探讨糖尿病肌肉代谢功能障碍的机制。用经过验证的计算模型进行的模拟将有助于确定可以用有效的实验设计进行检验的假设。

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.