The function and regulation of TBC1D1 in skeletal muscle metabolism.

TBC1D1在骨骼肌代谢中的功能和调节。

• 批准号: 7615265
• 负责人: Melissa Anne Chambers
• 金额: $ 4.52万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7615265
• 关键词: 5' -AMP-activated protein kinase; Adipocytes; Antibodies; Binding; Biological Assay; Calmodulin; Candidate Disease Gene; Classification; Complex; Data; Development; Diabetes Mellitus; Event; Exercise; Family; Family member; Future; GLUT4 gene; GTP Binding; GTPase-Activating Proteins; Gap Junctions; Gene Transfer; Glucose; Goals; Homeostasis; Human; Immunoblotting; Individual; Insulin; Intervention; Investigation; Laboratories; Lead; Mass Spectrum Analysis; Measures; Melissa; Molecular; Mus; Muscle; Muscle Contraction; Mutate; Mutation; Nature; Obesity; Phosphorylation; Phosphorylation Site; Play; Proteins; Radioactive; Regulation; Research; Role; Series; Signal Transduction; Signaling Molecule; Site; Skeletal Muscle; Stimulus; System; Testing; Tissues; Transgenic Mice; glucose disposal; glucose metabolism; glucose transport; glucose uptake; member; mouse model; muscle metabolism; mutant; novel; novel therapeutic intervention; overexpression; paralogous gene; protein function; public health relevance; rab GTP-Binding Proteins; response; skeletal; therapeutic development; upstream kinase; uptake

DESCRIPTION (provided by applicant): The goal of this study is to understand the function and regulatory mechanism of TBC1D1 (tre-2/USP6, BUB2, cdc16 domain family member 1) in skeletal muscle glucose metabolism. TBC1D1 has been identified as an obesity candidate gene in humans that potentially regulates GLUT4 translocation in adipocytes. TBC1D1 is an Akt-substrate 160 (AS160) paralog that is highly expressed in skeletal muscle and is responsive to insulin-, contraction-, and the AMP-activated protein kinase (AMPK) activator AICARstimulation. TBC1D1 may be a critical determinant of fuel homeostasis, yet nothing is known about the regulation and function of this protein in skeletal muscle. The systematic investigation of TBC1D1 could provide the rationale for development of novel therapeutic interventions for the treatment of diabetes. Exercise, i.e. contraction, leads to increased glucose uptake by skeletal muscle through a complex series of signaling events, including AS160 phosphorylation. Contraction also causes an increase in TBC1D1 phosphorylation. We hypothesize that TBC1D1 plays a critical role in skeletal muscle metabolism and is a nexus for convergent signaling by multiple stimuli that increase glucose uptake in muscle. My first aim will examine the upstream regulation of TBC1D1 in contraction- and insulin-stimulated skeletal muscle. To test the hypotheses for this aim, I plan to use a gene transfer system, immunoblotting, and existing transgenic mouse models. My second aim will examine TBC1D1 function in skeletal muscle metabolism. To investigate this aim I will continue to use a gene transfer system, immunoblotting and transgenic mouse models; in addition to a radioactive glucose transport assay. PUBLIC HEALTH RELEVANCE: This research will add to our understanding of skeletal muscle glucose metabolism and potentially identify novel targets for future development of therapeutic diabetes interventions.

描述（由申请人提供）：本研究的目的是了解骨骼肌葡萄糖代谢中TBC1D1（TRE-2/USP6，BUB2，CDC16域家族成员1）的功能和调节机制。在人类中，TBC1D1已被确定为肥胖的候选基因，可能调节脂肪细胞中的GLUT4易位。 TBC1D1是一种Akt-Substrate 160（AS160）旁系同源物，在骨骼肌中高度表达，对胰岛素，收缩 - 和AMP激活的蛋白激酶（AMPK）激活剂AICARANSIMANTIMANTIMATION响应。 TBC1D1可能是燃料稳态的关键决定因素，但对于该蛋白在骨骼肌中的调节和功能尚无知识。 TBC1D1的系统研究可以为开发用于治疗糖尿病的新型治疗干预措施提供基本原理。运动，即收缩，通过一系列复杂的信号事件（包括AS160磷酸化）导致骨骼肌的葡萄糖吸收增加。收缩还会导致TBC1D1磷酸化的增加。我们假设TBC1D1在骨骼肌代谢中起着至关重要的作用，并且是通过多种刺激会收敛信号的联系，从而增加了肌肉中葡萄糖摄取的摄取。我的第一个目标将检查收缩和胰岛素刺激的骨骼肌的TBC1D1的上游调节。为了测试此目标的假设，我计划使用基因转移系统，免疫印迹和现有的转基因小鼠模型。我的第二个目标将检查骨骼肌代谢中的TBC1D1功能。为了研究这一目标，我将继续使用基因转移系统，免疫印迹和转基因小鼠模型。除了放射性葡萄糖转运测定法。公共卫生相关性：这项研究将增加我们对骨骼肌葡萄糖代谢的理解，并有潜在地识别出治疗性糖尿病干预措施未来发展的新颖目标。