Myocardial Adenosine Receptors
心肌腺苷受体
基本信息
- 批准号:7868038
- 负责人:
- 金额:$ 40.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-07-11 至 2012-06-30
- 项目状态:已结题
- 来源:
- 关键词:AdenosineAdenosine A1 ReceptorAdenosine A2A ReceptorAdenosine A3 ReceptorAdrenergic AntagonistsAdrenergic ReceptorAffectAttenuatedBindingBiochemicalCardiacCardiac MyocytesDevelopmentDoctor of PhilosophyEnsureEventFunctional disorderG-Protein-Coupled ReceptorsHeartIschemiaKnockout MiceKnowledgeLaboratoriesMechanicsMediatingMembraneMetabolicMitogen-Activated Protein KinasesModificationMolecularMuscle CellsMyocardialMyocardiumPathway interactionsPhosphoric Monoester HydrolasesPhosphorylationPlayProtein IsoformsProtein KinaseProtein Kinase CProtein phosphataseProteinsPurinergic P1 ReceptorsRattusReceptor SignalingRegulationReportingRoleSarcolemmaSignal PathwaySignal TransductionTissuesTranslatingVentriculardesignheart functionhuman MAPK14 proteinmyocardial hypoxiaoperationprotein kinase C epsilonreceptorreceptors for activated C kinaseresponse
项目摘要
DESCRIPTION (provided by applicant): Adenosine receptors in the myocardium are known to play an important role in cardiac function in both the normal and diseased heart. Prior studies in this laboratory have focused on the cellular responses elicited upon stimulation of these receptors. In addition studies have been initiated to investigate how the receptor signals are translated into cellular responses in the heart. However, little is known regarding the details of the mechanisms involved in the elicited responses and the cross-regulation between cardiac adenosine receptors. We and others have reported that adenosine A1 receptor (A1R), adenosine A2A receptor (A2AR) and ?1 adrenergic receptor (?1 R) stimulation results in a number of effects in ventricular myocytes. The A1R serves an important antiadrenergic action, and the A2AR causes a positive inotropic response. Furthermore, together, the A2AR attenuates the A1 R-mediated antiadrenergic actions. However, little is known about the molecular events involved in adenosine receptor signal transduction mechanisms and interaction of the A1R and A2AR including the adenosine A3 receptor (A3R). Thus, the objective of this project will be to determine the molecular signal transduction mechanisms involving protein kinases and phosphatases in the A1R-, A2AR- and A3R-mediated actions in the heart. In addition the operation of these adenosine receptors in regulating cardiac mechanical and metabolic function will be determined. Using rat and A1 R, A2AR and double (A1R+A2AR) knockout mice ventricular myocytes, myocyte membranes and perfused hearts, the proposed studies should reveal: 1) Whether A1R stimulation causes protein kinase C isoforms to translocate and bind to RACK (receptor activated C kinase) proteins of the myocardial sarcolemma. Also the involvement of p38-MAPK (mitogen activated protein kinase) in the A1 R-mediated antiadrenergic action will be investigated, 2) The importance of the antiadrenergic action resulting from A3R stimulation and whether PKC isoforms are involved, 3) The way in which A2AR inhibits A1R mediated cardiac antiadrenergic actions, 4) The effect and importance of protein phosphatases in the cardiac effects produced by A1R, A2AR and A3R stimulation, and 5) How myocardial hypoxia and/or ischemia modifies the function of A1 R, A2AR and/or A3R, thereby increasing or reducing their roles in modulating heart function. The results obtained from these studies will provide new information regarding the molecular functioning of adenosine receptors in the myocardium. Additionally, the findings should significantly contribute to our knowledge of the molecular mechanisms of G- protein coupled receptor operation in the normal and diseased heart. Such information should be instrumental for the development of new therapies and agents to alleviate cardiac dysfunction.
描述(由申请人提供):已知心肌中的腺苷受体在正常和患病心脏的心脏功能中起重要作用。本实验室先前的研究集中在刺激这些受体后引起的细胞反应。此外,已经开始研究受体信号如何转化为心脏中的细胞反应。然而,很少有人知道的细节,在引起的反应和心脏腺苷受体之间的交叉调节的机制。我们和其他研究者报道,腺苷A1受体(A1 R)、腺苷A2 A受体(A2 AR)和腺苷受体(A1 R)在心肌细胞中均存在。1肾上腺素能受体(?1 R)刺激对心室肌细胞产生多种影响。A1 R起重要的抗肾上腺素能作用,A2 AR引起正性肌力反应。此外,A2 AR一起减弱A1 R介导的抗肾上腺素能作用。然而,关于腺苷受体信号转导机制和A1 R和A2 AR(包括腺苷A3受体(A3 R))相互作用所涉及的分子事件知之甚少。因此,本项目的目的将是确定涉及蛋白激酶和磷酸酶在A1 R-,A2 AR-和A3 R-介导的心脏活动的分子信号转导机制。此外,这些腺苷受体在调节心脏机械和代谢功能的操作将被确定。利用大鼠和A1 R、A2 AR及双(A1 R + A2 AR)基因敲除小鼠的心室肌细胞、心肌细胞膜和灌流心脏,研究A1 R刺激是否引起蛋白激酶C亚型移位并与心肌细胞膜RACK(receptor activated C kinase)蛋白结合。p38-MAPK也参与了(丝裂原活化蛋白激酶)在A1 R介导的抗肾上腺素能作用中的作用,2)A3 R刺激引起的抗肾上腺素能作用的重要性以及是否涉及PKC亚型,3)A2 AR抑制A1 R介导的心脏抗肾上腺素能作用的方式,4)蛋白磷酸酶在A1 R产生的心脏作用中的作用和重要性,A2 AR和A3 R刺激,和5)心肌缺氧和/或缺血如何改变A1 R、A2 AR和/或A3 R的功能,从而增加或减少它们在调节心脏功能中的作用。从这些研究中获得的结果将提供有关心肌腺苷受体分子功能的新信息。此外,这些发现将大大有助于我们了解G蛋白偶联受体在正常和病变心脏中的分子机制。这些信息应该有助于开发缓解心脏功能障碍的新疗法和药物。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JAMES G DOBSON其他文献
JAMES G DOBSON的其他文献
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{{ truncateString('JAMES G DOBSON', 18)}}的其他基金
ADENOSINE A1 AND A2 RECEPTORS IN THE MYOCARDIUM
心肌中的腺苷 A1 和 A2 受体
- 批准号:
6499100 - 财政年份:2001
- 资助金额:
$ 40.63万 - 项目类别:
ADENOSINE A1 AND A2 RECEPTORS IN THE MYOCARDIUM
心肌中的腺苷 A1 和 A2 受体
- 批准号:
6225862 - 财政年份:2001
- 资助金额:
$ 40.63万 - 项目类别:
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