Salvaging the ischemic myocardium: the role ephrinA1/EphA bidirectional signaling

挽救缺血心肌：ephrinA1/EphA 双向信号传导的作用

• 批准号: 8957796
• 负责人: Jitka A.I Virag
• 金额: $ 44.25万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8957796
• 关键词: Acute; Adhesions; Adhesives; Adult; Angiogenic Peptides; Apoptosis; Attenuated; Autophagocytosis; Autophagosome; Behavior; Binding; Blood Vessels; CISH gene; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Adhesion; Cell Survival; Cells; Cessation of life; Characteristics; Data; Destinations; Development; Disease; Elements; EphA Receptors; Equilibrium; Family; Feedback; Gene Expression; Genomics; Glean; HMGB1 gene; Heart; Hypoxia; Immunoglobulin G; In Vitro; Infarction; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Investigation; Ischemia; Leukocytes; Ligands; Ligation; Light; Location; Mediating; Membrane; Mitochondria; Mitochondrial Proteins; Molecular; Molecular Profiling; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; NF-kappa B; Oxidative Stress; Pathway interactions; Pattern; Performance; Phosphorylation; Process; Production; Protein Tyrosine Kinase; Receptor Protein-Tyrosine Kinases; Regenerative Medicine; Relative (related person); Reperfusion Injury; Reperfusion Therapy; Reporting; Respiration; Role; STAT3 gene; Severities; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Stress; Techniques; Therapeutic; Time; Tissue Engineering; Tissue Viability; Tissues; Wound Healing; axon guidance; cell motility; cell type; coronary artery occlusion; cytokine; differential expression; heart dimension/size; human FRAP1 protein; improved; in vivo; laser capture microdissection; mTOR inhibition; member; non-genomic; protective effect; protein expression; public health relevance; receptor; regional difference; research study; resilience; response; tumorigenesis

 DESCRIPTION (provided by applicant): Preserving tissue viability and performance following acute ischemia/reperfusion (I/R) would be best accomplished by simultaneously reducing the inflammatory response and enhancing cardiomyocyte resilience. Scores of cellular signaling molecules have been demonstrated to modulate exclusive elements of each of these wound healing processes but none have yet proven to oversee multiple facets concurrently. The EphrinA ligands and their cognate EphA receptors are part of the largest family of typically membrane-bound receptor tyrosine kinases (RTKs). They are differentially expressed in a variety of cells and activation or silencing of bi-directional signaling cascades can influences cel motility and/or adhesive/repulsive behavior. In the heart, we have observed that the ephrinA1 ligand, originally thought to be solely an angiogenic peptide and the only one of the 5 members of the A subclass that can bind to all EphA1-8 receptors, is expressed in murine cardiomyocytes. Our preliminary data indicate that exogenous ephrinA1-Fc administration at the time of coronary artery occlusion preserves cardiac function following I/R injury. Our preliminary data also implicate STAT3 as a signaling intermediate and further, regional differences in EphA-R expression relative to the site of injury may be accountable. More in depth investigation of the mechanisms by which these protective effects occur in vitro and in vivo will be valuable in evaluating the role of ephrinA1/EphA receptors and potential therapeutic value of ephrinA1-Fc in modulating these processes. Specifically, in vitro experiments using isolated adult cardiomyocytes +/- leukocytes pretreated with chimeric ephrinA1-Fc prior to hypoxia and reperfusion will enable comprehensive examination of the signaling mechanisms involved in reducing cardiomyocyte damage. In vivo, comparison of the composition and cell-specific expression characteristics in the infarct margin from the ligation site toward the apex in ephrinA1-Fc treated hearts versus controls will shed light on the mechanisms on protection. Information gleaned from these studies will provide the framework from which to extrapolate the potential capacity of selectively modulating ephrinA1 and EphA receptors to reduce myocardial injury and will be applicable to other ischemic diseases, regenerative medicine, and tissue engineering applications.

 描述（由适用提供）：通过简单地减少炎症反应并增强心肌细胞的弹性，可以最好地完成急性缺血/再灌注后的组织生存力和性能。已经证明了数分细胞信号分子可以调节每个伤口愈合过程的独特元素，但尚未证明没有证明可以同时监督多个方面。以弗里娜菌的配体及其同源EPHA受体是通常是膜结合的受体酪氨酸激酶（RTKS）的最大家族的一部分。它们在多种细胞中的表达方式有所不同，双向信号传导的激活或沉默可以影响CEL运动和/或粘合/或粘合/排斥行为。在心脏中，我们观察到，以埃菲纳1号配体最初被认为仅是一种血管生成肽，而A子类5个可以与所有Epha1-8受体结合的成员中的唯一是在鼠心肌细胞中表达的。我们的初步数据表明，冠状动脉闭塞时的外源Ephrina1-FC给药可保留I/R损伤后心脏功能。我们的初步数据还暗示了STAT3是信号传导中间体，而进一步，相对于伤害部位的EPHA-R表达的区域差异可能是负责任的。对这些受保护作用在体外和体内发生的机制进行了更深入的研究，对于评估ephrina1/epha受体的作用以及ephrina1-fc在调节这些过程中的潜在治疗价值方面将是有价值的。具体而言，使用孤立的成年心肌细胞+/-白细胞在缺氧之前预处理和再灌注的体外实验，将对涉及减少心肌细胞损害的信号传导机制进行全面检查。在体内，从连接部位的基础设施边缘的组成和细胞特异性表达特征比较以埃菲琳娜1-Fc处理的心脏与对照组的顶点的比较将阐明保护机制。从这些研究中收集的信息将提供一个框架，从而推断出选择性调节以Ephrina1和Epha受体以减少心肌损伤的潜在能力，并适用于其他缺血性疾病，再生医学和组织工程应用。

项目成果

Anatomical-Molecular Distribution of EphrinA1 in Infarcted Mouse Heart Using MALDI Mass Spectrometry Imaging.

• DOI: 10.1007/s13361-017-1869-7
• 发表时间: 2018-03
• 期刊: Journal of the American Society for Mass Spectrometry
• 影响因子: 3.2
• 作者: Lefcoski S;Kew K;Reece S;Torres MJ;Parks J;Reece S;de Castro Brás LE;Virag JAI
• 通讯作者: Virag JAI