Oxidative Capacity, Lipid Partitioning and Insulin Resistance in Skeletal Muscle

描述（由申请人提供）：这是一个为期五年的职业发展和研究计划，以研究与脂质诱导的胰岛素抵抗相关的机制。本提案的总体目标是确定脂质供应过剩对人体骨骼肌内脂质分配、线粒体容量和胰岛素敏感性的影响。 我将在Bret Goodpaster博士的指导下，主要在匹兹堡大学内分泌科完成拟议的职业发展和研究计划。我将接受临床研究方法和设计方面的广泛培训，以及评估体内胰岛素抵抗和人体肌肉活检标本中蛋白质和基因表达方法的具体培训。我将在肯塔基州大学的夏洛特彼得森博士的指导下接受原代肌细胞培养方法学的培训。将在匹兹堡大学药理学系Paul Baker和布鲁斯弗里曼博士的指导下进行骨骼肌脂质质谱测定的培训。这种具体的理论和实践培训直接关系到我未来进行肥胖和糖尿病研究的计划。更广泛地说，这些经验将建立在基础科学和临床研究的基础上，并有助于我作为一名独立的翻译科学家的发展。 我的初步数据表明，有氧运动改变骨骼肌脂质分配（增加甘油三酯，但降低甘油二酯和神经酰胺），这些变化可能与脂滴蛋白质的扰动和增强线粒体含量和/或能力。在这一拟议的培训期间，我打算延长这条线的研究，以探讨的可能性，在不同的脂质种类（甘油三酯，甘油二酯和神经酰胺）的脂肪酸组成的改变可能是在脂毒性介导的胰岛素抵抗的原因。急性体内研究脂质供应过剩，连同人类原代细胞培养技术，也将用于进一步探索途径介导改善胰岛素抵抗，包括线粒体的能力和脂滴基因和蛋白质表达的变化。 通过我的主要机构以外的合作的补充，匹兹堡大学是一个理想的环境，我专业发展和开始作为一个独立的翻译研究科学家成功的职业生涯。 公共卫生相关性：我将研究过多的脂质暴露于肌肉可能导致胰岛素抵抗的发展，这是2型糖尿病的主要原因。这些研究将帮助我们更好地了解运动和饮食可以预防或治疗2型糖尿病的方式。

DESCRIPTION (provided by applicant): This is a five-year career development and research program to study mechanisms associated with lipid induced insulin resistance. The overall objective of this proposal is to determine the effects of lipid oversupply on lipid partitioning, mitochondrial capacity and insulin sensitivity within human skeletal muscle. I will complete the proposed career development and research program primarily at the Division of Endocrinology of the University of Pittsburgh under the direction of Dr. Bret Goodpaster. I will receive extensive training in clinical research methods and design as well as specific training with methods to assess insulin resistance in vivo and protein and gene expression in human muscle biopsy specimens. I will receive training in primary myocyte culture methodology under the direction of Dr. Charlotte Peterson at the University of Kentucky. Training in mass spectroscopy determination of skeletal muscle lipids will take place under the direction of Drs. Paul Baker and Bruce Freemen in the Department of Pharmacology at the University of Pittsburgh. This specific theoretic and practical training is directly related to my future plans to conduct obesity and diabetes research. More broadly, these experiences will build upon a foundation of basic science and clinical research and aid in my development as an independent translational scientist. My preliminary data suggests that aerobic exercise alters skeletal muscle lipid partitioning (increased triglycerides but lower diacylglycerol and ceramides) and these changes may be related to perturbations in lipid droplet proteins and enhanced mitochondrial content and/or capacity. Within this proposed period of training, I intend to extend this line of research to explore the possibility that alterations in the fatty acid composition of various lipid species (triglyceride, diacylglycerol and ceramide) may be causative in lipotoxic mediated insulin resistance. Acute in vivo studies of lipid oversupply, together with human primary cell culture techniques, will also be utilized to further explore pathways mediating improved insulin resistance, including mitochondrial capacity and changes in lipid droplet gene and protein expression. Supplemented by collaborations outside my primary Institution, the University of Pittsburgh is an ideal setting for me to develop professionally and begin a successful career as an independent translational research scientist. PUBLIC HEALTH RELEVANCE: I will study how too much lipid exposure to muscle may lead to the development of insulin resistance, a primary cause of type 2 diabetes. These studies will help us better understand the way in which exercise and diet can prevent or treat type 2 diabetes.