Adenylate Kinase in Heart Energetics and Metabolic Signaling

腺苷酸激酶在心脏能量学和代谢信号传导中的作用

• 批准号: 7643332
• 负责人: PETRAS P DZEJA
• 金额: $ 37.75万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7643332
• 关键词: 5' -AMP-activated protein kinase; ATP sensitive potassium channel complex; Address; Adenine Nucleotides; Adenosine; Affinity Chromatography; Animals; Area; Cardiac; Cardiac Myocytes; Cell Nucleus; Cell membrane; Cell physiology; Cells; Complex; Coupling; Data; Energy Supply; Energy Transfer; Enzymes; Equilibrium; Event; Fluorescence Resonance Energy Transfer; Generations; Heart; Homeostasis; Hormonal; Human; Imaging Techniques; Insulin; Isoproterenol; Knowledge; Label; Mass Spectrum Analysis; Measurement; Mediating; Membrane; Metabolic; Metabolic stress; MgADP; MgATP; Microscopy; Mitochondria; Molecular; Myocardial; Myocardium; Myofibrils; Nucleotides; Performance; Positioning Attribute; Production; Property; Protein Isoforms; Protein Kinase; Proteomics; RNA Splicing; Reaction; Research Personnel; Response Elements; Role; Secure; Signal Transduction; Signaling Molecule; Stress; Stress Response Signaling; System; Techniques; Transgenic Organisms; adenylate kinase; adenylate kinase 1; base; biological adaptation to stress; nucleocytoplasmic transport; preconditioning; programs; response; sensor

DESCRIPTION (provided by applicant): Adenylate kinase(AK)-catalyzed energetic and AMP metabolic signaling (AK->AMP->AMP-sensors) is increasingly recognized among major stress-response elements in cardiac cells, critical in regulating diverse cellular processes. At present, however, molecular and cellular mechanisms regulating AK-catalyzed phosphotransfer, the main AMP signal generator, AK interactions with AMP-metabolic sensors and intracellular AMP signal dynamics, are largely unknown. We have obtained evidence that AK phosphotransfer communicates energetic signals from mitochondria to myofibrils, the nucleus and the plasma membrane, securing efficient energy supply and metabolic sensing. The central hypothesis of this proposal is that dynamics of AK phosphotransfer and AMP signal generation, regulated by functional, hormonal and metabolic state, promotes efficient cellular energetics and, by association with AMP-sensing modules, integrates AMP signal transduction into adaptive response to metabolic stress. This hypothesis is supported by preliminary data that indicate: 1) AK phosphotransfer flux and AMP metabolic pool size are regulated by the cell's functional and hormonal states and respond rapidly to metabolic stress; 2) AK1 associates/co-localizes with metabolic sensor AMP-activated protein kinase (AMPK); 3) AK1 deficiency is associated with defective AMP signaling and stress response. Based on this in Aim #1 we propose to define the cellular regulatory mechanisms coupling AK-catalyzed phosphotransfer, AMP signal dynamics and metabolic sensors response; In Aim #2, we will determine mechanisms and the significance of AK co- localization and molecular/functional interactions with AMPK in metabolic signaling. Finally, in Aim #3, we will determine the significance of the AK->AMP->AMP-sensors system in transducting metabolic signals triggering cardioprotective response. The proposed aims will be addressed using wilde type and transgenic AK1-deficient animals. AK phosphotransfer flux and AMP turnover will be quantified using 180-assisted 31P NMR and mass spectrometric techniques. Molecular, proteomic and imaging techniques will be employed to define AK intracellular interactions and new AMP signaling targets. As a long-term objective, this proposal will establish cellular and molecular mechanisms that regulate AK phosphotransfer and associated AMP signaling circuits sustaining efficient and stress tolerant myocardial energetics.

描述（由申请人提供）：腺苷酸激酶（AK）催化的能量和 AMP 代谢信号（AK->AMP->AMP 传感器）越来越被认为是心脏细胞中的主要应激反应元件，对于调节多种细胞过程至关重要。然而目前，调节 AK 催化磷酸转移（主要 AMP 信号发生器）、AK 与 AMP 代谢传感器的相互作用以及细胞内 AMP 信号动力学的分子和细胞机制在很大程度上尚不清楚。我们已经获得证据表明 AK 磷酸转移将能量信号从线粒体传递到肌原纤维、细胞核和质膜，确保有效的能量供应和代谢传感。该提案的中心假设是，AK 磷酸转移和 AMP 信号生成的动态受功能、激素和代谢状态的调节，促进有效的细胞能量学，并通过与 AMP 传感模块关联，将 AMP 信号转导整合到对代谢应激的适应性反应中。这一假设得到了初步数据的支持，这些数据表明：1) AK 磷酸转移通量和 AMP 代谢池大小受细胞功能和激素状态调节，并对代谢应激做出快速反应； 2) AK1 与代谢传感器 AMP 激活蛋白激酶 (AMPK) 关联/共定位； 3) AK1 缺陷与 AMP 信号传导和应激反应缺陷相关。基于这一目标#1，我们建议定义耦合 AK 催化磷酸转移、AMP 信号动力学和代谢传感器响应的细胞调节机制；在目标 #2 中，我们将确定代谢信号传导中 AK 共定位以及与 AMPK 的分子/功能相互作用的机制和重要性。最后，在目标 3 中，我们将确定 AK->AMP->AMP 传感器系统在转导触发心脏保护反应的代谢信号中的重要性。拟议的目标将使用王尔德型和转基因 AK1 缺陷动物来实现。 AK 磷酸转移通量和 AMP 周转率将使用 180 辅助 31P NMR 和质谱技术进行量化。将采用分子、蛋白质组和成像技术来定义 AK 细胞内相互作用和新的 AMP 信号传导靶点。作为一个长期目标，该提案将建立调节 AK 磷酸转移和相关 AMP 信号通路的细胞和分子机制，以维持高效和耐应激的心肌能量。