Systems Biology Investigation of Muscle Exercise Metabolism in Diabetes

描述（由申请人提供）：候选人是一名生物医学工程师，具有质量传输现象和代谢模型的专业知识。他的目标是成为多尺度系统生物学领域的一名研究者，该领域结合了计算建模和实验方法。通过先进的方法，他将量化细胞代谢与健康和状态疾病的生理反应相关的机制。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。研究训练强调定量理解细胞能量转移和代谢的调节在肌细胞和整个骨骼肌响应能量需求的对照和糖尿病大鼠。在对照和糖尿病心肌细胞中，细胞质和线粒体的生化特性和生物能量功能将被表征。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。受指导的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核磁共振技术和代谢专业知识的共同导师。这些导师将领导一个由研究人员组成的咨询委员会，他们的专业知识包括：a)代谢和生理系统的计算建模；B)运动与骨骼肌胰岛素抵抗；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）通过糖酵解能力与氧化能力的较高比例共同表达。胞质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之间的因果关系尚不明确。这种功能障碍可能与线粒体含量减少有关，而不是与内在缺陷或代谢调节改变有关。IR改善与线粒体含量、线粒体氧化功能或膜转运蛋白功能变化相关的可能机制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。测量肌肉收缩或胰岛素刺激的反应将包括生化和生物运输特性的变化，以及细胞质和线粒体中氧化和糖酵解系统的生物能量功能的变化。本研究结合体内外实验和骨骼肌能量代谢机制计算模型，探讨糖尿病患者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用有效的实验设计进行测试的假设。

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.