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: 7502607
• 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/7502607
• 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; Localized; Mass Spectrum Analysis; Measurement; Mediating; Membrane; Metabolic; Metabolic stress; MgADP; MgATP; Microscopy; Mitochondria; Molecular; Myocardial; Myocardium; Myofibrils; Nucleotides; Numbers; 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; size

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代谢信号传导（AK-> AMP-> AMP传感器）在心脏细胞中的主要应激反应元件中越来越认识到在调节多样的细胞过程中至关重要的。然而，目前，调节AK催化的磷酸转移的分子和细胞机制，主要AMP信号发生器，与AMP代谢传感器的AK相互作用和细胞内AMP信号动力学相互作用是未知的。我们获得了证据，表明AK磷酸转移从线粒体传达了能量信号到肌原纤维，细胞核和质膜，从而确保了有效的能量供应和代谢感应。该提案的中心假设是，受功能，激素和代谢状态调节的AK磷酸转移和AMP信号产生的动力学可促进有效的细胞能量，并通过与AMP敏感模块的结合，将AMP信号转导向代谢应激的适应性反应。该假设得到的初步数据支持：1）AK磷酸转移通量和AMP代谢池大小受细胞的功能和激素状态调节，并迅速对代谢胁迫做出迅速反应； 2）AK1 Associates/与代谢传感器AMP激活的蛋白激酶（AMPK）共定位； 3）AK1缺乏症与AMP信号传导和应力反应有缺陷有关。基于AIM＃1，我们建议定义耦合AK催化的磷酸转移，AMP信号动力学和代谢传感器响应的细胞调节机制；在AIM＃2中，我们将确定AK共同定位和与AMPK在代谢信号传导中的机制以及与AMPK的分子/功能相互作用的重要性。最后，在AIM＃3中，我们将确定AK-> AMP-> AMP传感器系统在转型代谢信号触发心脏保护反应中的重要性。拟议的目标将使用WILDE类型和转基因AK1缺乏动物来解决。 AK磷酸转移通量和AMP更新将使用180辅助31p NMR和质谱技术进行量化。将采用分子，蛋白质组学和成像技术来定义AK细胞内相互作用和新的AMP信号靶标。作为一个长期目标，该建议将建立细胞和分子机制，以调节AK磷酸转移和相关的AMP信号传导电路，以持续有效且耐应激的心肌能量。