Signaling Mechanisms of FGF2-induced Cardioprotection

FGF2 诱导的心脏保护作用的信号机制

• 批准号: 8316241
• 负责人: JOEL J SCHULTZ
• 金额: $ 42.15万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316241
• 关键词: Actomyosin Adenosinetriphosphatase; Acute; Acute myocardial infarction; Address; Animal Organ; Apoptotic; Biochemical; Biological; Calcium; Calcium Channel; Cardiac; 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; 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; Reperfusion Injury; Research; Reticulum; Role; Signal Pathway; Signal Transduction; Specificity; Stress; Study Section; Techniques; Testing; Therapeutic; Time; Transgenic Mice; Transgenic Organisms; Troponin; United States; Ventricular Function; antibody inhibitor; arm; base; gain of function; human NOS2A protein; indexing; insight; interdisciplinary approach; myocardial infarct sizing; novel; phospholamban; programs; public health relevance; receptor; research study; therapeutic gene; tissue repair; tool

DESCRIPTION (provided by applicant): 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 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. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is the primary cause of death in the United States. Understanding the molecular and cellular basis of cardioprotection is a necessary step towards developing FGF2 as a therapeutic strategy to limit the extent of acute myocardial infarction and protect the heart in the clinical setting.

描述（由申请人提供）：本提案的总体目标是研究FGF 2介导的心脏保护作用的分子靶点。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）信号是必需的FGF 2诱导的心脏保护。然而，这些信号通路介导FGF 2诱导的心肌保护作用对抗心肌功能障碍和梗死的下游靶点仍有待阐明。因此，我们将进行药理学，电生理学，亚蛋白质组学和综合生理学为基础的多学科方法，以确定已知的或新的基板的信号通路与FGF 2诱导的心脏保护。该提案将评估与FGF 2活性或心脏保护相关的激酶的已知下游底物的参与，并通过亚蛋白质组学分析确定FGF 2诱导的心脏保护的新靶点。研究计划将把蛋白质和细胞水平的基本信息与整个器官/动物水平的信息结合起来。这些研究还将使我们能够直接将心肌梗死和缺血后心室功能恢复的变化与FGF 2的生物活性及其蛋白激酶途径的特定下游靶点联系起来。为了确定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，电生理学和分子方法。类似的技术将用于确定FGF 2在肌（内）浆网（SR）蛋白和收缩器水平调节钙稳态中的重要性，最终影响缺血后心脏功能。初步数据表明，线粒体，SR和收缩器作为FGF 2诱导的心脏保护作用的靶点，这些细胞器的候选和新底物将通过磷酸化蛋白质组学（免疫印迹和2-D凝胶/MS）技术进行询问。该提案的结果将为FGF 2诱导的心脏保护提供新的见解，并可能最终导致FGF 2作为缺血性心脏病治疗的药理学或遗传学发展。 公共卫生相关性：心血管疾病是美国的主要死亡原因。了解心脏保护的分子和细胞基础是开发FGF 2作为治疗策略以限制急性心肌梗死的程度并在临床环境中保护心脏的必要步骤。