Big MAP Kinase 1-Cx 43 Signaling in Ischemia Injury

缺血损伤中的大 MAP 激酶 1-Cx 43 信号转导

基本信息

批准号：
7390795
负责人：
JAY YANG
金额：
$ 35.6万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7390795
关键词：
ATP Synthesis Pathway Adenoviruses Adult Affect Appendix Area Arts Attenuated Binding Budgets Burn injury Calpain Cardiac Cardiac Myocytes Cardiovascular Physiology Cardiovascular system Cell Respiration Cells Cellular biology Chemicals Clinical Collaborations Communication Condition Connexin 43 Connexins Contractile Proteins Coupling Cytoplasm Cytoprotection Data Elements Elevation Endopeptidases Exhibits Family Functional disorder Gap Junctions Goals Grant Heart Heart Ventricle Impairment Injury Institution Investigation Ions Ischemia Ischemic Preconditioning Joints Knockout Mice Laboratories Lead Letters Link MAP Kinase Gene Maps Mediating Metabolic Mitochondria Mitogen Activated Protein Kinase 1 Mitogen-Activated Protein Kinases Modeling Molecular Biology Mus Myocardial Myocardial Ischemia Neurosciences Numbers Nutrient Oxidative Stress Patient Care Peptide Hydrolases Phospholipase Phosphoproteins Phosphorylation Phosphotransferases Physiological reperfusion Play Preparation Productivity Property Proteins Protons Publications Pump Range Recovery Recovery of Function Recruitment Activity Regulation Reperfusion Injury Reperfusion Therapy Research Research Personnel Role Signal Transduction Signal Transduction Pathway Techniques Thinking Time Tissues Transgenic Mice Transgenic Organisms Universities Viral Vector Work Yang abstracting attenuation base cell injury clinically relevant design improved in vivo inhibitor/antagonist innovation interest member mitochondrial dysfunction novel novel therapeutics preconditioning programs protein degradation research study small molecule upstream kinase

项目摘要

DESCRIPTION (provided by applicant): Ca2+ overload is a major cause of myocardial cell damage and cardiac dysfunction in ischemic heart diseases. Studies with gap junction coupling inhibitors and connexin (Cx) 43 knock out mice suggest that Cx43 is important in regulating ischemia/ reperfusion (IR)- induced cellular Ca2+ overload. Cx43 gap junction coupling is regulated by several kinases including mitogen-activated-protein (MAP) kinases. Since ischemic preconditioning improves the recovery of cardiac function after IR-injury and also activates Big- MAPK 1 (BMK1), a member of MARK, we hypothesized that activation of BMK1 induced by preconditioning phosphorylates Cx43, decreases gap junction coupling, and reduces ischemia/ reperfusion-induced cellular Ca2+ overload. Key data in support of our hypothesis include: 1} BMK1 phosphorylates and associates with Cx43, and leads to gap junction uncoupling, 2) Cx43 phosphorylation is increased in cardiac-specific transgenic mice expressing the constitutively active form of the upstream kinase MEK5 (CA-MEK5) which specifically activates BMK1, 3) CA-MEK5 transgenic hearts exhibit a profoundly accelerated recovery of pump function after IR-injury in a Langendorff model. We will study the role of BMK1 and Cx43 phosphorylation in post-ischemic cardiac dysfunction with the following specific aims: Aim 1: Define the role of BMK1 in Cx43 phosphorylation and subsequent Cx43 gap junction uncoupling. Aim 2: Define the role of BMK1 in Cx43 phosphorylation and the effect of Cx43 phosphorylation on IR- induced Ca2+ overload, subsequent calpain activity, and mitochondrial dysfunction. Aim 3: Determine the role of BMK1 and subsequent Cx43 phosphorylation in IR-injury, in vivo, and Aim 4: Investigate the role of BMK1-Cx43 signaling in chemical preconditioning. The broad-based experimental approach should allow us to conclude the importance of BMK1-Cx43 signaling in IR-injury. The long-range goal of this line of investigation is to discover a novel therapeutic strategy for reducing IR-injury.

描述（申请人提供）：Ca2+超载是缺血性心脏病中心肌细胞损伤和心功能障碍的主要原因。对间隙连接偶联抑制剂和连接蛋白 (Cx) 43 敲除小鼠的研究表明，Cx43 在调节缺血/再灌注 (IR) 诱导的细胞 Ca2+ 超载中发挥着重要作用。 Cx43 间隙连接偶联受多种激酶调节，包括丝裂原激活蛋白 (MAP) 激酶。由于缺血预处理改善了IR损伤后心脏功能的恢复，并且还激活了MARK的成员Big-MAPK 1 (BMK1)，我们假设预处理诱导的BMK1的激活使Cx43磷酸化，减少间隙连接偶联，并减少缺血/再灌注诱导的细胞 Ca2+ 过载。支持我们假设的关键数据包括：1} BMK1 磷酸化并与 Cx43 结合，导致间隙连接解偶联，2) 在表达上游激酶 MEK5 (CA-) 的组成型活性形式的心脏特异性转基因小鼠中，Cx43 磷酸化增加。 MEK5) 特异性激活 BMK1, 3) CA-MEK5 转基因心脏在 IR 损伤后表现出泵功能的显着加速恢复兰根多夫模型。我们将研究 BMK1 和 Cx43 磷酸化在缺血后心功能障碍中的作用，具体目标如下：目标 1：定义 BMK1 在 Cx43 磷酸化和随后的 Cx43 间隙连接解偶联中的作用。目标 2：定义 BMK1 在 Cx43 磷酸化中的作用以及 Cx43 磷酸化对 IR 诱导的 Ca2+ 超载、随后的钙蛋白酶活性和线粒体功能障碍的影响。目标 3：确定 BMK1 和随后的 Cx43 磷酸化在体内 IR 损伤中的作用，目标 4：研究 BMK1-Cx43 信号传导在化学预处理中的作用。基础广泛的实验方法应该使我们能够得出 BMK1-Cx43 信号传导在 IR 损伤中的重要性。这一系列研究的长期目标是发现一种减少红外线损伤的新治疗策略。