Myocardial ischemic activation of the Akt pathway

Akt 通路的心肌缺血激活

基本信息

批准号：
7247821
负责人：
STEPHEN C ARMSTRONG
金额：
$ 26.23万
依托单位：
SANFORD RESEARCH/USD
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：
2004-08-16 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7247821
关键词：
1-Phosphatidylinositol 3-Kinase Adaptor Signaling Protein Apoptosis Apoptotic Binding Biological Assay Biological Preservation Cardiac Myocytes Cell Death Co-Immunoprecipitations Complex Development Disruption Dystroglycan Endocytosis Fluorescence Focal Adhesion Kinase 1 G-Protein-Coupled Receptors Glycogen Synthase Kinase 3 Glycogen Synthase Kinases HSPB1 gene Heat shock proteins Heat-Shock Proteins 70 In Vitro Infarction Injury Ischemia Ischemic Preconditioning MAP Kinase Gene MAP3K5 gene MAPK14 gene Mediating Mediator of activation protein Membrane Modality Modeling Molecular Molecular Chaperones Muscle Cells Myocardial Myocardial Ischemia Myocardium Pathway interactions Phospho-Specific Antibodies Phosphorylation Phosphotransferases Physiological reperfusion Proteins Purpose Receptor Activation Regulation Relative (related person)Reperfusion Therapy Reporting Role Scaffolding Protein Signal Pathway Signal Transduction Signaling Molecule Therapeutic gel mobility shift assay heat-shock factor 1 preconditioning programs src Homology Region 2 Domain transcription factor

项目摘要

DESCRIPTION (provided by applicant): The PI-3 kinase/Akt pathway is a potential mediator of the cardioprotection provided by preconditioning. The primary purpose of this proposal is the identification of the cardioprotective end-effectors that are activated by the PI-3 kinase/Akt pathway. Heat shock factor-1 (HSF-1) is a transcription factor that initiates the expression of heat shock protein 70 (HSP70), a molecular chaperone that has been associated with the cardioprotection provided by ischemic preconditioning. A role for NFkB in ischemic preconditioning has also been demonstrated. HSF-1 and NFkB activation are negatively regulated by GSK-3 and this regulation is abrogated by the phosphorylation of glycogen synthase kinase (GSK)-3b by Akt. The relative role of GSK-3 in the inhibition of HSF-1 and NFkB will be determined. We will also examine an alternative Akt substrate apoptosis signal regulating kinase 1 (ASK1). We will determine the association of Akt with ASK1 and the subsequent Akt mediated phosphorylation of ASK-1 at Ser83, negatively regulating the activation of p38MAPK and Jun kinase and the initiation of apoptosis. This might involve the interaction of ASK1 with 14-3-3 protein. We will also examine the association of Akt with the small heat shock protein, HSP27, which functions as a scaffolding protein for Akt. We will determine the ability of HSP27, in association with Akt, to facilitate the anti-apoptotic function of Akt. The signaling pathways that initiate PI-3 kinase activation during myocardial ischemia and regulate Akt activity have not been elucidated. Disruption of the dystroglycan complex in muscle cells decreases Akt and GSK-3 phosphorylation, initiating apoptosis. We propose that b-dystroglycan (bDG) assembles a complex of signaling molecules that allows an association with and activation of the p85 subunit of PI-3K, initiating Akt phosphorylation. We propose that PI-3 kinase/Akt activation requires endocytosis of this membrane associated the bDG complex. This is analogous to the recent report that ischemic preconditioning is mediated by an endosomal G-protein coupled receptor activation pathway. These studies will afford a molecular understanding of the mechanisms of irreversible ischemic myocardial injury and the end effectors of preconditioning. This may allow the development of pharmacologic modalities for the therapeutic delay of myocardial ischemia and the preservation of myocardium jeopardized by infarction.

描述（由申请人提供）：PI-3 激酶/Akt 通路是预处理提供的心脏保护作用的潜在介质。该提案的主要目的是鉴定由 PI-3 激酶/Akt 通路激活的心脏保护性末端效应器。热休克因子-1 (HSF-1) 是一种转录因子，可启动热休克蛋白 70 (HSP70) 的表达，热休克蛋白 70 是一种与缺血预处理提供的心脏保护作用相关的分子伴侣。 NFkB 在缺血预处理中的作用也已得到证实。 HSF-1 和 NFkB 的激活受到 GSK-3 的负向调节，并且这种调节可通过 Akt 磷酸化糖原合酶激酶 (GSK)-3b 来消除。将确定 GSK-3 在抑制 HSF-1 和 NFkB 中的相对作用。我们还将检查另一种 Akt 底物凋亡信号调节激酶 1 (ASK1)。我们将确定 Akt 与 ASK1 的关联以及随后 Akt 介导的 ASK-1 Ser83 磷酸化，从而负向调节 p38MAPK 和 Jun 激酶的激活以及细胞凋亡的启动。这可能涉及 ASK1 与 14-3-3 蛋白的相互作用。我们还将研究 Akt 与小热休克蛋白 HSP27 的关联，HSP27 充当 Akt 的支架蛋白。我们将确定 HSP27 与 Akt 结合促进 Akt 抗凋亡功能的能力。心肌缺血期间启动 PI-3 激酶激活并调节 Akt 活性的信号通路尚未阐明。破坏肌肉细胞中的肌营养不良聚糖复合物会降低 Akt 和 GSK-3 的磷酸化，从而引发细胞凋亡。我们提出 b-肌营养不良聚糖 (bDG) 组装信号分子复合物，允许与 PI-3K 的 p85 亚基关联并激活，从而启动 Akt 磷酸化。我们认为 PI-3 激酶/Akt 激活需要与 bDG 复合物相关的膜的内吞作用。这与最近的报道类似，即缺血预处理是由内体 G 蛋白偶联受体激活途径介导的。这些研究将为不可逆缺血性心肌损伤的机制和预处理的末端效应器提供分子理解。这可能有助于开发延迟治疗心肌缺血和保护受到梗塞危害的心肌的药理学方法。