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

Ca2/钙调蛋白激酶在骨骼肌葡萄糖转运和生长中的作用。

• 批准号: 7513055
• 负责人: Carol Ann Witczak
• 金额: $ 8.91万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7513055
• 关键词: 5' -AMP-activated protein kinase; AICA ribonucleotide; Address; Affinity; Age; Aging; Atrophic; Attenuated; Biochemical; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium/calmodulin-dependent protein kinase; Chemicals; Data; Denervation; Development; Diabetes Mellitus; Disease; Functional disorder; Gene Transfer; Goals; Growth; Individual; Knockout Mice; Lead; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Microtubules; Modeling; Molecular; Muscle; Muscle Fibers; Muscular Atrophy; Numbers; Pathway interactions; Pharmacologic Substance; Phosphorylation; Phosphotransferases; Physiological; Play; Process; Protein Biosynthesis; Protein-Serine-Threonine Kinases; Proteins; Regulation; Research Personnel; Role; Signal Pathway; Signal Transduction; Signaling Protein; Sirolimus; Skeletal Muscle; Weight; Work; calcium--calmodulin dependent protein kinase kinase alpha; calmodulin-dependent protein kinase I; glucose metabolism; glucose transport; glucose uptake; in vivo; innovation; loss of function; muscle hypertrophy; novel; programs; research study; response; size; wasting

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.

描述（由申请人提供）：骨骼肌代谢功能障碍和萎缩是许多破坏性疾病（包括糖尿病和癌症）的显着特征，并且也可能因衰老和缺乏活动而发生在健康个体中。细胞内 Ca2+ 是骨骼肌许多过程（包括代谢和生长）的关键调节因子，但令人惊讶的是，Ca2+ 调节这些关键功能的信号传导机制仍然很大程度上未知。我最近的博士后研究工作发现，Ca2+ 敏感的丝氨酸/苏氨酸激酶、Ca2+/钙调蛋白依赖性蛋白激酶激酶α (CaMKKα) 是骨骼肌中收缩诱导的葡萄糖转运的新型调节剂。重要的是，我们发现 CaMKKalpha 独立于 AMP 激活蛋白激酶（一种已经参与此过程的信号蛋白）调节葡萄糖转运。因此，CaMKKα 介导葡萄糖转运的下游机制尚不清楚，而该底物的识别是特定目标 1 的重点。此外，我的研究中令人兴奋的初步数据表明 CaMKKα 在骨骼肌的调节中具有积极作用通过哺乳动物雷帕霉素靶蛋白（mTOR）信号级联反应进行质量传递，这是一种调节蛋白质合成的途径。因此，具体目标 2 和 3 的目标（我的独立研究的重点）是确定 CaMKKalpha 在骨骼肌生长和蛋白质合成调节中的作用。这项工作的意义在于，阐明参与这些关键过程的信号蛋白应该有助于开发出与许多疾病（包括糖尿病和癌症）相关的肌肉代谢和消耗性疾病的新疗法。公开描述：代谢功能受损和肌肉质量损失是包括糖尿病和癌症在内的大量破坏性疾病的显着特征，并且也可能发生在健康个体中，以应对衰老和缺乏活动。我们的目标是确定细胞内蛋白 Ca2+/钙调蛋白依赖性蛋白激酶激酶 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应该有助于开发出更好的药物治疗方法，用于治疗与多种疾病（包括糖尿病和癌症）相关的肌肉代谢和消耗性疾病。