Role of Ca2+/calmodulin kinases in skeletal muscle glucose transport and growth.

描述（由申请人提供）：骨骼肌代谢功能障碍和萎缩是许多毁灭性疾病的突出特征，包括糖尿病和癌症，也可能发生在健康个体中，以应对衰老和缺乏运动。细胞内Ca2+是骨骼肌许多过程的关键调节剂，包括代谢和生长，但令人惊讶的是，Ca2+调节这些关键功能的信号机制在很大程度上仍然未知。我最近的博士后研究工作已经确定了Ca2+敏感丝氨酸/苏氨酸激酶，Ca2+/钙调素依赖蛋白激酶激酶α (CaMKKalpha)，作为收缩诱导的骨骼肌葡萄糖运输的新调节剂。重要的是，我们发现CaMKKalpha调节葡萄糖转运独立于amp激活的蛋白激酶，这是一种已经参与这一过程的信号蛋白。因此，CaMKKalpha介导葡萄糖转运的下游机制尚不清楚，而这种底物的鉴定是Specific Aim 1的重点。此外，从我的研究中获得的令人兴奋的初步数据表明，CaMKKalpha在通过哺乳动物雷帕霉素（mTOR）信号级联调控骨骼肌质量方面具有积极作用，雷帕霉素是一种调节蛋白质合成的途径。因此，Specific Aims 2和3的目标是确定CaMKKalpha在骨骼肌生长和蛋白质合成调节中的作用，这是我独立研究的重点。这项工作的意义在于，阐明参与这些关键过程的信号蛋白将导致与许多疾病（包括糖尿病和癌症）相关的肌肉代谢和消耗障碍的新治疗方法的发展。公众描述：代谢功能受损和肌肉量减少是包括糖尿病和癌症在内的大量破坏性疾病的突出特征，也可能发生在健康个体中，以应对衰老和缺乏运动。我们的目标是确定细胞内蛋白Ca2+/钙调素依赖性蛋白激酶α在骨骼肌葡萄糖代谢和生长调节中的作用。了解这些关键过程所涉及的途径，将有助于开发出更好的药物治疗与许多疾病（包括糖尿病和癌症）相关的肌肉代谢和消耗紊乱。

DESCRIPTION (provided by applicant): Skeletal muscle metabolic dysfunction and atrophy are prominent features of a number of devastating diseases, including diabetes and cancer, and can also occur in healthy individuals in response to aging and inactivity. Intracellular Ca2+ is a key regulator of many processes in skeletal muscle, including metabolism and growth, yet surprisingly the signaling mechanisms by which Ca2+ regulates these critical functions remain largely unknown. Recent work from my postdoctoral studies has identified the Ca2+-sensitive serine/ threonine kinase, Ca2+/calmodulin-dependent protein kinase kinase alpha (CaMKKalpha), as a novel regulator of contraction-induced glucose transport in skeletal muscle. Importantly, we found that CaMKKalpha regulates glucose transport independent of the AMP-activated protein kinase, a signaling protein already implicated in this process. Thus, the downstream mechanism by which CaMKKalpha mediates glucose transport is not known, and the identification of this substrate is the focus of Specific Aim 1. In addition, exciting preliminary data from my studies suggest a positive role for CaMKKalpha in the regulation of skeletal muscle mass via the mammalian target of rapamycin (mTOR) signaling cascade, a pathway that regulates protein synthesis. Thus, the goal of Specific Aims 2 and 3, the focus of my independent research studies, is to determine the role of CaMKKalpha in the regulation of skeletal muscle growth and protein synthesis. The significance of this work is that elucidation of the signaling proteins involved in these key processes should lead to the development of new treatments for muscle metabolic and wasting disorders associated with many diseases, including diabetes and cancer. PUBLIC DESCRIPTION: Impaired metabolic function and loss of muscle mass are prominent features of a large number of devastating diseases, including diabetes and cancer, and can also occur in healthy individuals in response to aging and inactivity. Our goal is to determine the role that the intracellular protein, Ca2+/calmodulin-dependent protein kinase kinase alpha, plays in the regulation of skeletal muscle glucose metabolism and growth. Understanding the pathways involved in these key processes should lead to the development of better pharmaceutical treatments for muscle metabolic and wasting disorders associated with numerous diseases, including diabetes and cancer.