Role of Erythropoietin receptor signaling in heart

描述（由申请人提供）：促红细胞生成素（Epo）通过与其在红系祖细胞上表达的细胞表面受体EpoR结合来调节红细胞的产生。 Epo 的生物学作用不仅限于调节哺乳动物红细胞生成。 除了胎儿肝脏红细胞生成受损之外，Epo 或 EpoR 缺失的小鼠胚胎还表现出心脏形态发生缺陷、血管网络异常以及心内膜​​和心肌细胞凋亡增加。 尽管 Epo-EpoR 功能与正常心脏发育有关，但人们对 Epo-EpoR 信号在心脏中的直接生理作用知之甚少。 我们研究了 Epo 对心脏的影响，并检验了 Epo 可能在整体心脏缺血再灌注期间发挥心脏保护作用的假设。 我们发现，在离体灌注心脏实验模型中，Epo 表现出正性肌力和心脏保护作用，可显着改善缺血再灌注损伤后的缺血后收缩恢复。 本提案的目的是研究心脏中的 Epo-EpoR 信号传导，重点关注 Epo 保护心肌细胞免受缺血损伤的能力所涉及的机制。 该提案的具体目标是 1)。 目的 研究 Epo 对心脏缺血再灌注期间梗塞面积和细胞凋亡的影响，以检验 Epo 在离体大鼠心脏灌注实验模型中可以减少梗塞面积和心肌细胞凋亡的假设。 2）。 表征培养的原代心肌细胞和离体灌注心脏中的 Epo-EpoR 信号转导通路，以检验心肌细胞的 Epo 处理可能导致功能性下游 EpoR 信号通路激活的假设，包括磷脂酰肌醇 3-激酶 (PI3-K) 和蛋白激酶 B/Akt 通路。 3）。目的 研究缺血再灌注期间 Epo 介导的心脏保护作用所涉及的信号机制，以检验 Epo 的心脏保护作用可能与 EpoR 介导的 PI3 激酶/Akt 通路激活相关的假设。 这些研究将开始表征心脏中功能性 EpoR 信号通路的特征，研究 Epo 心脏保护作用的机制，并为未来评估重组人 Epo 作为心脏保护疗法在急性缺血性心脏损伤综合征中的应用的临床试验奠定基础。

DESCRIPTION (provided by applicant): Erythropoietin (Epo) regulates the production of red blood cells by binding to its cell surface receptor EpoR expressed on erythroid progenitor cells. The biologic effects of Epo are not limited to the regulation of mammalian erythropoiesis. In addition to impaired fetal liver erythropoiesis, Epo or EpoR-null mouse embryos exhibit defects in cardiac morphogenesis, abnormalities in the vascular network and increased apoptosis in endocardium and myocardium. Although Epo-EpoR function has been implicated in normal cardiac development, little is known about direct physiologic effects of Epo-EpoR signaling in the heart. We investigated cardiac effects of Epo and tested the hypothesis that Epo may exert a cardioprotective effect during global cardiac ischemia followed by reperfusion. We found that Epo exhibits a positive inotropic and cardioprotective effect with significantly improved post-ischemia contractile recovery following ischemiareperfusion injury in an experimental model of isolated, perfused hearts. The objective of this proposal is to investigate Epo-EpoR signaling in the heart with focus on the mechanisms involved in the ability of Epo to protect cardiomyocytes from ischemic damage. The specific aims of this proposal are 1). To examine the effect of Epo on infarct size and apoptosis during cardiac ischemia-reperfusion to test the hypothesis that Epo may reduce infarct size and cardiomyocyte apoptosis in an experimental model of isolated rat heart perfusion. 2). To characterize Epo-EpoR signal transduction pathways in cultured primary cardiomyocytes and in ex vivo perfused hearts to test the hypothesis that Epo treatment of cardiomyocytes may result in activation of functional downstream EpoR signaling pathways including phosphatidylinositol 3-kinase (PI3-K) and protein kinase B/Akt pathway. 3). To investigate signaling mechanisms involved in Epo-mediated cardioprotective effect during ischemia-reperfusion to test the hypothesis that the cardioprotective effects of Epo may be associated with EpoR-mediated activation of PI3-kinase/Akt pathway. These studies will begin to characterize functional EpoR signaling pathways in the heart, investigate the mechanisms of the cardioprotective effects of Epo and lay the groundwork for future clinical trials evaluating the use of recombinant human Epo as cardioprotective therapy, in syndromes of acute ischemic cardiac injury.