Myocardial ischemic activation of the Akt pathway

Akt 通路的心肌缺血激活

• 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
• 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

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途径是预处理提供的心脏保护的潜在介体。该提案的主要目的是鉴定由PI-3激酶/AKT途径激活的心脏保护端效应。热休克因子1（HSF-1）是转录因子，它启动热休克蛋白70（HSP70）的表达，这是一种与缺血性预处理提供的心脏保护相关的分子伴侣。还已经证明了NFKB在缺血性预处理中的作用。 HSF-1和NFKB激活受GSK-3的负调节，该调节被Akt糖基因合酶激酶（GSK）-3B的磷酸化消除。 GSK-3在抑制HSF-1和NFKB中的相对作用将得到确定。我们还将检查调节激酶1的替代AKT底物凋亡信号（ASK1）。我们将确定AKT与ASK1的关联以及随后的Akt介导的SER83 ASK-1的磷酸化，对P38MAPK和JUN激酶的激活以及凋亡的开始负面调节。这可能涉及Ask1与14-3-3蛋白的相互作用。我们还将检查AKT与小热休克蛋白HSP27的关联，该蛋白可以用作AKT的脚手架蛋白。我们将确定HSP27与AKT相关的能力，促进AKT的抗凋亡功能。在心肌缺血期间启动PI-3激酶激活和调节AKT活性的信号传导途径尚未阐明。肌肉细胞中多胶糖复合物的破坏会降低AKT和GSK-3磷酸化，从而启动凋亡。我们建议B-Dystroglycan（BDG）组装了信号分子的复合物，该复合物允许与PI-3K的p85亚基的关联和激活，从而启动Akt磷酸化。我们建议PI-3激酶/AKT激活需要该膜与BDG复合物相关的内吞作用。这类似于最近的报告，即缺血性预处理是由内体G蛋白偶联受体激活途径介导的。这些研究将对不可逆性脑性心肌损伤的机制和预处理的最终效应子有分子的理解。这可以允许发展药理学方式，以使心肌缺血的治疗延迟以及通过梗塞危害危险的心肌保存。