Signaling mechanisms of FGF2-induced cardioprotection

FGF2 诱导心脏保护的信号机制

基本信息

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
项目类别：
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

项目摘要

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）：该提案的总体目的是研究成纤维细胞生长因子2（FGF2）的心脏保护作用的信号传导机制。 FGF2触发以在缺血期间引起心脏保护的途径尚不清楚。但是，有证据表明，在许多细胞类型中，FGF2可以通过蛋白激酶C（PKC），有丝分裂原激活的蛋白激酶（MAPK）或一氧化氮（NO）和ATP敏感钾（KATP）通道发出信号。包括细胞生长，血管舒张和血管生成。所有这些信号通路也已显示在心脏保护中很重要。将建立一种广泛的多学科方法，该方法将结合多种技术（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），并将在分子水平将遗传信息与整个器官/动物水平的生理信息整合在一起。为了确定FGF2介导的心脏保护的分子机制，我们将评估已知可以介导FGF2信号传导的蛋白激酶（PKC和MAPK）活性的模式，或者已与心脏保护的发展有关。这将通过确定在野生型和FGF2转基因小鼠心脏中和缺血再灌注损伤之前和期间明显改变这些途径的方法，并将这些分子/生化变化与心脏功能的缺血后恢复相关联。 FGF2的慢性心脏表达对一氧化氮合酶（NOS）mRNA，蛋白质，酶活性和细胞分布的影响，将对所有三种同工型（ENOS，INOS和NNOS）进行系统定义，这是首次提供彻底的表征在小鼠心脏中的这些变化中。此外，PKC，MAPK，NOS和KATP通道的药理抑制剂对心脏功能和梗塞大小的缺血后恢复的影响将与FGF2的生物学作用有关。将评估这些信号通路的整合，以确定激活是否以平行或串行方式发生以调节FGF2诱导的心脏保护。该提案的结果将为FGF2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，并应促进新型药理学和/或基因治疗策略的发展，从而改善并增强易感心脏病患者对缺血性心脏抗性的心脏抵抗力。