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，研究与脂肪诱导的胰岛素抵抗相关的机制。这项建议的总体目标是确定脂质供应过剩对人体骨骼肌内脂质分区、线粒体容量和胰岛素敏感性的影响。 我将在布雷特·古德巴斯特博士的指导下，主要在匹兹堡大学内分泌学系完成拟议的职业发展和研究计划。我将接受广泛的临床研究方法和设计方面的培训，以及评估体内胰岛素抵抗和人体肌肉活组织标本的蛋白质和基因表达方法的具体培训。我将在肯塔基大学夏洛特·彼得森博士的指导下接受原代心肌细胞培养方法学方面的培训。在匹兹堡大学药理学系保罗·贝克博士和布鲁斯·弗里曼博士的指导下，将进行骨骼肌脂类物质光谱测定方面的培训。这一具体的理论和实践培训直接关系到我未来开展肥胖和糖尿病研究的计划。更广泛地说，这些经历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翻译科学家的发展。 我的初步数据表明，有氧运动改变了骨骼肌脂类分配(增加了甘油三酯，但降低了二酰甘油和神经酰胺)，这些变化可能与脂滴蛋白的扰动和线粒体含量和/或能力的增加有关。在这个拟议的培训期间，我打算扩展这一研究路线，以探索各种脂质物种(甘油三酯、二酰甘油和神经酰胺)的脂肪酸组成变化可能是脂毒性介导的胰岛素抵抗的原因。脂质过剩的急性体内研究，以及人类原代细胞培养技术，也将被用来进一步探索介导胰岛素抵抗改善的途径，包括线粒体能力和脂滴基因和蛋白质表达的变化。 匹兹堡大学辅以我的主要机构以外的合作，对我来说是一个理想的环境，让我在专业上发展，并作为一名独立的翻译研究科学家开始成功的职业生涯。 公共卫生相关性：我将研究肌肉中过多的脂肪暴露可能会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.