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（由适用提供）：类型2糖尿病当前苦苦挣扎> 2580万美国人，而美国医疗保健系统损失超过2450亿美元。它是一种以高血糖，高胰岛素血症和胰岛素抵抗的特征，骨骼肌是负责体内胰岛素介导的葡萄糖摄取的主要组织。尽管肌肉在维持血糖体内稳态方面的重要性，但目前尚无针对独立于胰岛素的肌肉葡萄糖摄取的糖尿病的药物治疗。抵抗运动/肌肉收缩活动刺激葡萄糖吸收肌肉；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降低2型糖尿病血糖水平的有效策略。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的分子，细胞或代谢机制，这些机制调节了胰岛素独立的葡萄糖摄取，并测试靶向这些机制是否有效地改善2型糖尿病中的高血糖。 Recent evidence has now implemented 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 promise new target for treating impaired muscle glucose uptake in type 2 diabetes.不幸的是，CAMKK调节肌肉葡萄糖摄取能力的基础机制尚不清楚。该提案的特定目标是确定细胞内信号传导蛋白[即camkk在肌肉中激活的底物；确定CAMKK刺激肌肉葡萄糖的利用方式；并确定对持续的CAMKK介导的肌肉葡萄糖吸收的简单激活是否需要进行能源消耗过程。为了实现这些目标，将采用最先进的方法和方法的组合，包括使用ATP模拟筛选肌肉中的新型Camkk底物，体内肌肉基因转移/电穿孔，以允许小鼠肌肉中基因的快速，瞬态表达，并产生肌肉特异性的Camkkkkkkkkkk敲除小鼠。预计拟议的研究将阐明CAMKK刺激胰岛素敏感和抗胰岛素耐药性肌肉中葡萄糖摄取能力的细胞内机制；朝着开发2型糖尿病的新疗法的关键第一步，旨在刺激胰岛素独立的葡萄糖吸收到骨骼肌中。