Signaling Mechanisms of FGF2-induced Cardioprotection

FGF2 诱导的心脏保护作用的信号机制

• 批准号: 7899445
• 负责人: JOEL J SCHULTZ
• 金额: $ 39.25万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-11-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7899445
• 关键词: Actomyosin Adenosinetriphosphatase; Acute; Acute myocardial infarction; Address; Animal Organ; Apoptotic; Biological; Calcium; Calcium Channel; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular Physiology; Cause of Death; Cell Death Signaling Process; Cell Survival; Cessation of life; Chronic; Clinical; Contractile Proteins; Data; Development; Exhibits; Fibroblast Growth Factor; Fibroblast Growth Factor 2; Fibroblast Growth Factor 2 Overexpression; Functional disorder; Gel; Genetic; Goals; Growth Factor; Heart; Homeostasis; Immunoblotting; Infarction; Injury; Ischemia; Knock-out; Lead; MAPK14 gene; MAPK8 gene; Mediating; Mediator of activation protein; Methodology; Methods; Mitochondria; Mitochondrial Proteins; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Target; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Myosin ATPase; Nitric Oxide; Organ; Organelles; Pathway interactions; Phosphotransferases; Physiological; Post-Translational Protein Processing; Potassium; Progress Reports; Property; Protein Isoforms; Protein Kinase; Protein Kinase C; Proteins; Proteomics; Recovery; Regulation; Reperfusion Injury; Research; Reticulum; Role; Signal Pathway; Signal Transduction; Specificity; Stress; Study Section; Techniques; Testing; Therapeutic; Time; Transgenic Mice; Transgenic Organisms; Troponin; United States; Upper arm; Ventricular Function; Wound Healing; antibody inhibitor; base; citrate carrier; gain of function; human NOS2A protein; indexing; insight; interdisciplinary approach; novel; phospholamban; programs; receptor; research study; therapeutic gene; tool

The overall goal of this proposal is to investigate the molecular target(s) underlying FGF2-mediated cardioprotection. Findings from the original proposal indicate that nitric oxide (NO), protein kinase C (PKC), and mitogen-activated protein kinase (MAPK) signaling are necessary for FGF2-induced cardioprotection. Yet, the downstream targets by which these signaling pathways mediate FGF2- induced cardioprotection against myocardial dysfunction and infarction remain to be elucidated. Therefore, we will undertake a pharmacological-, electrophysiological-, subproteomic- and integrative physiological-based multidisciplinary approach to identify known or novel substrates of the signaling pathways associated with FGF2-induced cardioprotection. The proposal will evaluate the involvement of known downstream substrates of kinases that have been affiliated with FGF2 activity or with cardioprotection, and the identify novel targets of FGF2-induced cardioprotection by subproteomic analysis. The research plan will integrate basic information at the protein and cellular level with information at the whole organ/animal level. These studies will also enable us to directly relate changes in myocardial infarction and post-ischemic recovery of ventricular function to the biological activity of FGF2 and to specific downstream targets of its protein kinase pathways. To ascertain the involvement of ATP-sensitive potassium (KATP) channels in FGF2-induced cardioprotection, we will employ pharmacologic, electrophysiological, and molecular methods. Similar techniques will be used to determine the importance of FGF2 in regulating calcium homeostasis at the level of sarco(endo)plasmic reticulum (SR) proteins and contractile apparatus, ultimately influencing post- ischemic cardiac function. With preliminary data implicating the mitochondria, SR, and contractile apparatus as targets of FGF2-induced cardioprotection, candidate and novel substrates of these organelles will be interrogated via phosphoproteomic (immunoblotting and 2-D gel/MS) techniques. Results of this proposal will provide new insights into FGF2-induced cardioprotection and may eventually lead to the pharmacologic or genetic development of FGF2 as a therapy against ischemic heart disease.

本提案的总体目标是研究FGF 2介导的细胞凋亡的分子靶点。 心脏保护最初的研究结果表明，一氧化氮（NO），蛋白激酶C (PKC)和丝裂原活化蛋白激酶（MAPK）信号转导是FGF 2诱导的细胞凋亡所必需的。 心脏保护然而，这些信号通路介导FGF 2 - 3的下游靶点是： 诱导的针对心肌功能障碍和梗塞的心脏保护仍有待阐明。 因此，我们将进行药理学-，电生理学-，亚蛋白质组学-和整合 基于生理学的多学科方法来鉴定信号传导的已知或新底物 与FGF 2诱导的心脏保护相关的途径。该提案将评估参与 已知的与FGF 2活性相关的激酶的下游底物，或 心脏保护，并通过亚蛋白质组学鉴定FGF 2诱导的心脏保护的新靶点 分析.该研究计划将整合蛋白质和细胞水平的基本信息， 整个器官/动物水平的信息。这些研究也将使我们能够直接联系到 心肌梗死和缺血后心室功能恢复的生物学变化 FGF 2活性及其蛋白激酶途径的特异性下游靶点。查明 ATP敏感性钾（KATP）通道参与FGF 2诱导的心脏保护，我们将 采用药理学、电生理学和分子学方法。将使用类似的技术 确定FGF 2在调节钙稳态水平的重要性， 肌（内）质网（SR）蛋白和收缩装置，最终影响后 缺血性心脏功能初步数据表明，线粒体，SR，和收缩 作为FGF 2诱导的心脏保护作用的靶点的装置，这些装置的候选和新底物 细胞器将通过磷酸蛋白质组学（免疫印迹和2-D凝胶/MS）技术进行分析。 该提案的结果将为FGF 2诱导的心脏保护提供新的见解， 最终导致FGF 2的药理学或遗传学发展，作为抗缺血性疾病的疗法， 心脏病