Signaling mechanisms of FGF2-induced cardioprotection

FGF2 诱导心脏保护的信号机制

• 批准号: 7247819
• 负责人: JOEL J SCHULTZ
• 金额: $ 35.85万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7247819
• 关键词: Active Biological Transport; Acute myocardial infarction; Animal Organ; Biochemical; Biological; Biological Process; Blood Vessels; Cardiac; Cardiovascular Physiology; Cell membrane; Chronic; Clinical; Complex; Data; Development; Extracellular Signal Regulated Kinases; Fibroblast Growth Factor; Fibroblast Growth Factor 2; Fibroblast Growth Factor 2 Overexpression; Fibroblast Growth Factor Receptors; Functional disorder; Gene Targeting; Genetic; Goals; Heart; Infarction; Injury; Ischemia; Ischemic Preconditioning; Knock-out; Knockout Mice; Lead; Localized; MAPK14 gene; Mechanics; Mediating; Mediator of activation protein; Messenger RNA; Methods; Mitochondria; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Genetics; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Nature; Nitric Oxide; Nitric Oxide Synthase; Numbers; Pathway interactions; Patients; Pattern; Pharmacology; Phospholipase C; Physiological; Physiology; Potassium; Production; Property; Protein Isoforms; Protein Kinase; Protein Kinase C; Protein Kinase C Inhibitor; Proteins; Recovery; Reperfusion Injury; Research; Research Personnel; Resistance; Role; Signal Pathway; Signal Transduction; Signaling Protein; Specificity; Stress; Stretching; Techniques; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Transgenic Organisms; Vasodilation; Ventricular; Work; Wound Healing; angiogenesis; antibody inhibitor; base; body system; cell growth; cell type; citrate carrier; gain of function; improved; indexing; insight; interdisciplinary approach; mitogen-activated protein kinase p38; mouse model; novel; programs; receptor; research study; response; size; stress-activated protein kinase 1; therapeutic gene; tool

DESCRIPTION (provided by applicant): The overall objective of this proposal is to investigate the signaling mechanisms underlying the cardioprotective effect of fibroblast growth factor-2 (FGF2). The pathway(s) triggered by FGF2 to elicit protection in the heart during ischemia is unknown. However, evidence indicates that in many cell types, FGF2 can signal through protein kinase C (PKC), mitogen-activated protein kinase (MAPK), or nitric oxide (NO) and ATP-sensitive potassium (KATP) channels to mediate certain biological functions including cellular growth, vasodilation, and angiogenesis. All of these signaling pathways have also been shown to be important in cardioprotection. A broad multidisciplinary approach will be established that will combine diverse techniques (integrative physiology, molecular genetics, gene-targeted/transgenic mouse models, and pharmacology) and will integrate genetic information at the molecular level with physiological information at the whole organ/animal level. To ascertain the molecular mechanism(s) for FGF2-mediated cardioprotection, we will assess the patterns in activity of protein kinases (PKC and MAPK) that are either known to mediate FGF2 signaling or have been implicated in the development of cardioprotection. This will be done by determining which of these pathways is markedly altered prior to and during ischemia-reperfusion injury in wildtype and FGF2 transgenic mouse hearts and correlating these molecular/biochemical changes with post ischemic recovery of cardiac function and myocardial infarction. The effects of chronic cardiac expression of FGF2 upon nitric oxide synthase (NOS) mRNA, protein, enzymatic activity, and cellular distribution will be systematically defined for all three isoforms (eNOS, iNOS, and nNOS), providing for the first time a thorough characterization of these changes in the mouse heart. Furthermore, the effect of pharmacological inhibitors of PKC, MAPK, NOS, and KATP channels, on post-ischemic recovery of cardiac function and infarct size will be investigated and correlated with the biological actions of FGF2. Integration of these signaling pathways will be evaluted to determine whether activation occurs in a parallel or serial fashion to modulate FGF2-induced cardioprotection. The results from this proposal will provide important new insights into molecular and signaling mechanisms of FGF2-induced cardioprotection and should facilitate the development of novel pharmacological and/or gene therapeutic strategies that improve and enhance cardiac resistance to ischemia in susceptible cardiac patients.

描述（由申请人提供）：本提案的总体目标是研究成纤维细胞生长因子-2（FGF 2）心脏保护作用的信号传导机制。在缺血期间由FGF 2触发以在心脏中引起保护的途径是未知的。然而，有证据表明，在许多细胞类型中，FGF 2可以通过蛋白激酶C（PKC）、促分裂原活化蛋白激酶（MAPK）或一氧化氮（NO）和ATP敏感性钾（KATP）通道来介导某些生物学功能，包括细胞生长、血管舒张和血管生成。所有这些信号通路也被证明在心脏保护中很重要。将建立一个广泛的多学科方法，结合联合收割机各种技术（综合生理学、分子遗传学、基因靶向/转基因小鼠模型和药理学），并将分子水平的遗传信息与整个器官/动物水平的生理信息相结合。为了确定FGF 2介导的心脏保护的分子机制，我们将评估已知介导FGF 2信号传导或与心脏保护的发展有关的蛋白激酶（PKC和MAPK）的活性模式。这将通过确定这些途径中的哪一个在野生型和FGF 2转基因小鼠心脏的缺血-再灌注损伤之前和期间显著改变，并将这些分子/生物化学变化与心脏功能和心肌梗死的缺血后恢复相关联来完成。慢性心脏表达FGF 2对一氧化氮合酶（NOS）mRNA，蛋白质，酶活性和细胞分布的影响将系统地定义为所有三种亚型（eNOS，iNOS和nNOS），首次提供了这些变化在小鼠心脏的彻底表征。此外，将研究PKC、MAPK、NOS和KATP通道的药理学抑制剂对缺血后心脏功能恢复和梗死面积的影响，并将其与FGF 2的生物学作用相关联。将评价这些信号传导通路的整合，以确定激活是否以平行或串行方式发生，以调节FGF 2诱导的心脏保护作用。该提案的结果将为FGF 2诱导的心脏保护的分子和信号传导机制提供重要的新见解，并应促进新的药理学和/或基因治疗策略的发展，改善和增强心脏对易感心脏病患者缺血的抵抗力。