Signaling Mechanisms of FGF2-induced Cardioprotection

FGF2 诱导的心脏保护作用的信号机制

基本信息

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
项目类别：
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

项目摘要

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）：该提案的总体目标是研究 FGF2 介导的心脏保护作用的分子靶点。最初提案的结果表明，一氧化氮 (NO)、蛋白激酶 C (PKC) 和丝裂原激活蛋白激酶 (MAPK) 信号传导对于 FGF2 诱导的心脏保护是必需的。然而，这些信号通路介导 FGF2 诱导的针对心肌功能障碍和梗塞的心脏保护作用的下游靶点仍有待阐明。因此，我们将采取基于药理学、电生理学、亚蛋白质组学和综合生理学的多学科方法来识别与 FGF2 诱导的心脏保护相关的信号通路的已知或新底物。该提案将评估与 FGF2 活性或心脏保护相关的已知激酶下游底物的参与情况，并通过亚蛋白质组分析确定 FGF2 诱导的心脏保护的新靶点。该研究计划将蛋白质和细胞水平的基本信息与整个器官/动物水平的信息整合起来。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 FGF2 的生物活性及其蛋白激酶途径的特定下游靶标联系起来。为了确定 ATP 敏感钾 (KATP) 通道在 FGF2 诱导的心脏保护中的作用，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 FGF2 在调节肌（内）质网（SR）蛋白和收缩器官水平的钙稳态中的重要性，最终影响缺血后心脏功能。初步数据表明线粒体、SR 和收缩装置是 FGF2 诱导的心脏保护的靶标，这些细胞器的候选和新型底物将通过磷酸蛋白质组学（免疫印迹和 2-D 凝胶/MS）技术进行研究。该提案的结果将为 FGF2 诱导的心脏保护提供新的见解，并可能最终导致 FGF2 作为治疗缺血性心脏病的药物的药理学或遗传发展。公共卫生相关性：心血管疾病是美国的主要原因。了解心脏保护的分子和细胞基础是开发 FGF2 作为限制急性心肌梗死程度并在临床环境中保护心脏的治疗策略的必要步骤。