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：
7782265
负责人：
JOEL J SCHULTZ
金额：
$ 40.43万
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 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7782265
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 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 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 Wound Healing antibody inhibitor arm base citrate carrier gain of function human NOS2A protein indexing insight interdisciplinary approach novel phospholamban programs public health relevance receptor research study therapeutic gene 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介导的心脏保护基础的分子靶标。原始建议的发现表明，一氧化氮（NO），蛋白激酶C（PKC）和有丝分裂原激活的蛋白激酶（MAPK）信号对于FGF2诱导的心脏保护是必需的。然而，这些信号通路介导FGF2诱导的心肌功能障碍和梗塞的心脏保护性的下游靶标仍尚待阐明。因此，我们将采用一种药理学 - 电生理学，亚蛋白质学和基于综合性生理的多学科方法，以鉴定与FGF2诱导的心脏保护相关的信号通路的已知或新底物。该建议将评估与FGF2活性或心脏保护相关的已知的下游激酶的下游底物的参与，并通过亚蛋白质组分析确定FGF2诱导的心脏保护的新靶标。该研究计划将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在一起。这些研究还将使我们能够直接将心肌梗死的变化和心室功能的缺血后恢复与FGF2的生物学活性以及其蛋白激酶途径的特定下游靶标有关。为了确定ATP敏感钾（KATP）通道参与FGF2诱导的心脏保护作用，我们将采用药理，电生理和分子方法。类似的技术将用于确定FGF2在调节SARCO（ENDO）浆网（SR）蛋白质和收缩式蛋白质水平上调节钙稳态的重要性，最终影响缺血后心脏功能。通过涉及线粒体，SR和收缩式设备作为FGF2诱导的心脏保护的靶标的初步数据，这些细胞器的候选和新型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FGF2诱导的心脏保护提供新的见解，并最终可能导致FGF2的药理学或遗传发育，作为针对缺血性心脏病的治疗。公共卫生相关性：心血管疾病是美国死亡的主要原因。理解心脏保护的分子和细胞基础是开发FGF2作为一种治疗策略的必要步骤，以限制急性心肌梗塞的程度并在临床环境中保护心脏。