CHRONIC HYPOXIA AND RESISTANCE TO MYOCARDIAL ISCHEMIA

慢性缺氧和抗心肌缺血

• 批准号: 7251641
• 负责人: JOHN E BAKER
• 金额: $ 26.61万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7251641
• 关键词: 1-Phosphatidylinositol 3-Kinase; ATP Synthesis Pathway; Apoptosis; Asses; Binding; Biological; Biology; Blood; Blood Platelets; Cardiac; Cardiotonic Agents; Chronic; Co-Immunoprecipitations; Development; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; HMR 1098; Heart; Human; Hypoxia; In Vitro; Indium; Infant; Ischemia; Lead; Literature; MAPK14 gene; MAPK8 gene; Measures; Mechanics; Mediating; Mediation; Mediator of activation protein; Megakaryocytes; Membrane Potentials; Messenger RNA; Mitochondria; Modeling; Myocardial Infarction; Myocardial Ischemia; Necrosis; Oryctolagus cuniculus; Pathway interactions; Phosphotransferases; Physiological; Physiological reperfusion; Proteins; Ras/Raf; Recovery; Recruitment Activity; Relative (related person); Reperfusion Therapy; Research Personnel; Resistance; Respiration; Risk; Signal Pathway; Signal Transduction; Thrombopoietin; Tissues; Western Blotting; human MPL protein; in vivo; mitochondrial membrane; novel; novel therapeutics; programs; protein expression; receptor

DESCRIPTION (provided by applicant): Thrombopoietin (Tpo) is the primary physiologic regulator of megakaryocyte and platelet development through the Tpo receptor mpl. Recently we have made the novel and serendipitous observation that Tpo is an extraordinarily potent cardioprotective agent. These original observations may cause a paradigm shift in how we view the mechanisms and biological effects of Tpo. Thus the overall objective of this proposal is to define the intracellular signaling pathways by which Tpo confers early and delayed cardioprotection. Whereas there is a substantial body of literature regarding the mpl receptor composition, distribution and signaling in platelet function, there is no information about the pathway by which binding of Tpo to mpl confers cardioprotection and how this pathway is recruited by hypoxia in the heart. We hypothesize that activation of the Tpo receptor triggers pro-survival pathways and suppresses apoptosis to confer early and delayed cardioprotection by opening of mitochondrial KATp channels and/or mitochondria! KCa channels. Specifically we shall: 1) Determine the pathways that confer early cardioprotection by Tpo. We shall determine whether Tpo signals through its receptor (mpl) to activate the pro-survival kinase signaling cascade: JAK/STAT, Ras, Raf, phosphatidylinositol-3-OH kinase (PI3K)/Akt, PKC, JNK, p38 MARK and p42/44 MARK. We shall determine whether protection by Tpo given immediately following reperfusion acts by activating the pro-survival RISK pathway and whether Tpo protects the chronically hypoxic heart. 2) Determine the relative importance of the mitochondrial KATP channel, KCa channel and the sarcolemmal KATP channel in early cardioprotection produced by Tpo. We shall determine if Tpo signaling in early cardioprotection is mediated by opening of mitochondrial KATP and KCa channels. We shall measure mitochondrial membrane potential, respiration and ATP synthesis in mitochondria isolated from Tpo-treated hearts to determine the relationship between KATP channels to mitochondrial function. 3) Determine the effect of chronic hypoxia on the expression of Tpo and the Tpo receptor (mpl) in rabbit and human heart. We shall utilize our model of chronic hypoxia to determine in both infant human and rabbit hearts whether adaptation to chronic hypoxia increases expression of message and protein for mpl and circulating levels of platelets. 4) Determine the mediators of delayed cardioprotection produced by Tpo. We shall determine if "NO acts as a mediator of delayed cardioprotection by Tpo. We shall then determine if mediation of delayed cardioprotection by Tpo occurs by opening sarcolemmal and/or mitochondrial KATP channels. The results of these studies are expected to have an impact on our understanding of the biology of Tpo in heart and may lead to the development of new therapeutics for the treatment of myocardial infarction.

描述（由申请人提供）：血小板蛋白（TPO）是通过TPO受体MPL的巨核细胞和血小板发育的主要生理调节剂。最近，我们对TPO是一种非常有效的心脏保护剂进行了小说和偶然的观察。这些原始观察结果可能会导致我们如何看待TPO的机制和生物学效应的范式转移。因此，该提案的总体目的是定义TPO提早和延迟心脏保护的细胞内信号通路。尽管关于MPL受体组成，分布和血小板功能中的信号传导有大量文献，但没有关于TPO与MPL结合的途径的信息，可以使MMPL置于心脏保护以及该途径如何由心脏中缺氧募集。我们假设TPO受体触发促生存的途径的激活可以通过开放线粒体KATP通道和/或线粒体抑制凋亡以提早和延迟心脏保护的凋亡！ KCA频道。具体而言，我们应：1）确定通过TPO提出早期心脏保护的途径。我们应确定通过其受体（MPL）激活促生存性激酶信号级联的TPO信号是否：JAK/STAT，RAS，RAF，磷脂酰肌醇3-OH激酶（PI3K）/AKT/AKT/AKT，PKC，PKC，JNK，JNK，P38 MARK和P42 MARK和P42和P42 MARK和P42 MARK和P42 MARK和P42 /44标记。我们应确定再灌注后立即通过激活生存风险途径以及TPO保护慢性低氧心脏的TPO保护。 2）在TPO产生的早期心脏保护中，确定线粒体KATP通道，KCA通道和Sarcolemmal KATP通道的相对重要性。我们将确定通过开放线粒体KATP和KCA通道介导的早期心脏保护中的TPO信号传导。我们将测量从TPO处理的心脏分离的线粒体中的线粒体膜电位，呼吸和ATP合成，以确定KATP通道与线粒体功能之间的关系。 3）确定慢性缺氧对兔和人心中TPO受体（MPL）表达的影响。我们将利用我们的慢性缺氧模型来确定婴儿和兔子心中是否适应慢性缺氧是否会增加信息和蛋白质的表达和蛋白质的MPL和循环水平。 4）确定TPO产生的延迟心脏保护的介体。我们应确定“没有作为TPO延迟心脏保护的介体的行为。然后，我们将通过打开肌膜和/或线粒体KATP通道来确定是否会通过TPO进行延迟的心脏保护调解。这些研究的结果预计会影响我们对心脏中TPO生物学的理解，可能导致开发新的治疗疗法来治疗心肌梗塞。