Calmodulin Kinases and Control of Skeletal Muscle Glucose Metabolism

钙调蛋白激酶和骨骼肌葡萄糖代谢的控制

基本信息

批准号：
10096147
负责人：
Carol Ann Witczak
金额：
$ 35.66万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-20 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10096147
关键词：
Calmodulin Kinases Control Skeletal Muscle

项目摘要

DESCRIPTION (provided by applicant): Type 2 diabetes currently afflicts >25.8 million Americans and costs the US healthcare system over $245 billion/year. It is a disease characterized by hyperglycemia, hyperinsulinemia, and insulin resistance in skeletal muscle, the primary tissue responsible for insulin-mediated glucose uptake in the body. Despite the importance of muscle in maintaining blood glucose homeostasis, there are currently no pharmaceutical treatments for diabetes that target muscle glucose uptake independent of insulin. Resistance exercise/muscle contractile activity stimulates glucose uptake into muscle; and importantly in type 2 diabetes the ability of exercise to stimulate muscle glucose uptake remains functional. Thus, targeting the mechanisms underlying exercise/contraction-mediated muscle glucose uptake is an effective strategy for lowering blood glucose levels in type 2 diabetes. Unfortunately, these mechanisms are not well understood. The long-term goals of this research are to identify the molecular, cellular or metabolic mechanisms within muscle that regulate insulin-independent glucose uptake and to test whether targeting those mechanisms is effective at ameliorating hyperglycemia in type 2 diabetes. Recent evidence has now implicated the Ca2+-activated, serine/threonine kinase, Ca2+/calmodulin-dependent protein kinase kinase  (CaMKK) as a key regulator of exercise-sensitive, insulin-independent muscle glucose uptake, suggesting that CaMKK may be a promising new target for treating impaired muscle glucose uptake in type 2 diabetes. Unfortunately, the mechanism(s) underlying the ability of CaMKK to regulate muscle glucose uptake remains unclear. The specific objectives of this proposal are to identify the intracellular signaling protein(s) [i.e. substrate(s)] activated by CaMKK in muscle; to determine how CaMKK stimulates muscle glucose utilization; and to determine whether simultaneous activation of an energy consuming process is necessary for sustained CaMKK -mediated muscle glucose uptake. To achieve these objectives, a combination of state-of-the-art approaches and methodologies will be applied including use of an ATP analog to screen for novel CaMKK substrates in muscle, in vivo muscle gene transfer/electroporation to allow for the rapid, transient expression of genes in mouse muscle, and generation of a muscle-specific CaMKK knockout mouse. It is anticipated that the proposed research will elucidate the intracellular mechanism(s) governing the ability of CaMKK to stimulate glucose uptake in both insulin-sensitive and insulin-resistant muscle; a critical first step towards the development of new treatments for type 2 diabetes aimed at stimulating insulin-independent glucose uptake into skeletal muscle.

描述（由申请人提供）：2 型糖尿病目前困扰着超过 2580 万美国人，每年给美国医疗保健系统造成的损失超过 2450 亿美元。这种疾病的特征是骨骼肌中出现高血糖、高胰岛素血症和胰岛素抵抗，而骨骼肌是导致糖尿病的主要组织。尽管肌肉在维持血糖稳态方面很重要，但目前还没有针对肌肉葡萄糖摄取的糖尿病药物治疗。抗阻运动/肌肉收缩活动刺激肌肉中的葡萄糖摄取；重要的是，在 2 型糖尿病中，运动刺激肌肉葡萄糖摄取的能力仍然有效，因此，针对运动/收缩介导的肌肉葡萄糖摄取的机制是一种有效的策略。不幸的是，这些机制尚不清楚，这项研究的长期目标是确定肌肉内调节非胰岛素依赖性葡萄糖摄取的分子、细胞或代谢机制。针对这些机制的目标是可有效改善 2 型糖尿病的高血糖。最近的证据表明 Ca2+ 激活的丝氨酸/苏氨酸激酶、Ca2+/钙调蛋白依赖性蛋白激酶激酶 α (CaMKKα) 是运动敏感、胰岛素非依赖性肌肉的关键调节因子。葡萄糖摄取，表明 CaMKKα 可能是治疗 2 型糖尿病肌肉葡萄糖摄取受损的一个有前景的新靶标。 CaMKKα 调节肌肉葡萄糖摄取的能力尚不清楚，该提案的具体目标是鉴定肌肉中 CaMKKα 激活的细胞内信号蛋白 [即底物]，以确定 CaMKKα 如何刺激。肌肉葡萄糖利用；并确定能量消耗过程的同时激活对于持续的 CaMKKα 介导的肌肉葡萄糖摄取是否必要，需要结合最先进的方法和技术。将应用的方法包括使用 ATP 类似物筛选肌肉中的新型 CaMKKα 底物、体内肌肉基因转移/电穿孔以允许基因在小鼠肌肉中快速、瞬时表达，以及生成肌肉特异性 CaMKKα预计拟议的研究将阐明控制 CaMKKα 刺激胰岛素敏感和胰岛素抵抗肌肉中葡萄糖摄取的能力的细胞内机制；开发 2 型糖尿病新疗法，旨在刺激骨骼肌对不依赖于胰岛素的葡萄糖的摄取。