Cytoskeletal-Based Survival Pathways in Myocardium

心肌中基于细胞骨架的生存途径

• 批准号: 7338343
• 负责人: Richard Vander Heide
• 金额: $ 30.1万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-02 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7338343
• 关键词: Acute myocardial infarction; Adenoviruses; Area; Biochemical; Cardiac Myocytes; Caspase; Cell Death; Cell Survival; Cells; Cessation of life; Clinical; Cytoskeleton; Data; Disruption; Down-Regulation; Focal Adhesion Kinase 1; Focal Adhesions; Goals; Heart; Heat Stress Disorders; Heat-Shock Response; Heating; Hyperplasia; Hypertrophy; In Vitro; Individual; Injury; Intervention; Ischemia; Laboratories; Lead; Mediator of activation protein; Membrane; Microscopic; Molecular; Muscle Cells; Myocardial; Myocardial Infarction; Myocardium; Organ Model; Pathway interactions; Physiological reperfusion; Play; Process; Proteins; Proto-Oncogene Proteins c-akt; Rattus; Receptor Activation; Recombinants; Reperfusion Injury; Reperfusion Therapy; Role; Series; Signal Pathway; Signal Transduction; Signaling Protein; Stress; Testing; Tissues; base; cytochrome c; extracellular; in vivo; innovation; member; mortality; mouse model; prevent; receptor; research study; response; stressor

DESCRIPTION (provided by applicant): Protecting myocytes from death is the best way to lower the mortality associated with myocardial infarction. Despite the description of many interventions capable of protecting myocytes from lethal injury, the potential promise of applying these interventions in the clinical arena has remained unfulfilled due in part to a lack of an integrative understanding of the heart's response to stress. One specific area that remains poorly understood is how myocardial stress is transduced across the sarcolemmal membrane into a protective signal at the level of the individual myocyte. The long term goal of our laboratory is to understand better the cellular and molecular mechanism(s) responsible for cardioprotective signaling at the level of the myocyte. The goal of this proposal is to demonstrate that signaling through a cytoskeletal based pathway can be activated to enhance myocyte survival against lethal ischemic injury. Focal adhesion kinase (FAK) has become recognized as a key mediator of cell survival signaling pathways in heart as well as other tissues. Recent data has demonstrated that an integrated signaling pathway exists involving FAK, the cytoskeleton, and other subcelluar signaling proteins that can be amplified or stimulated by stress; specifically ischemia/reperfusion, heat shock, and/or membrane receptor stimulation. This proposal will test the hypothesis that myocardial stress, either directly or through receptor activation, amplifies a cytoskeletal- based signaling cascade that results in prolonged myocyte survival. Specific aims of the proposal will demonstrate that: 1) activation of FAK plays a central role in the response to extracellular myocardial stress; 2) activation of the cytoskeletal-based pathway results in cardioprotection through activation of Akt; and 3) activation of the pathway occurs in intact hearts and may provide a common pathway for many described cardioprotective interventions. The specific cell survival proteins activated by stress will be evaluated in a series of integrated experiments utilizing recombinant adenoviruses, biochemical, and microscopic analysis of cultured cardiomyocytes, and will be confirmed in intact hearts using isolated perfused rat and mouse models of ischemic cell death. Characterization of the underlying mechanism(s) of this survival/adaptive pathway will enhance our understanding of irreversible injury and may lead to new and innovative clinical strategies in the therapy of acute myocardial infarction.

描述（由申请人提供）：保护心肌免受死亡是降低与心肌梗塞相关的死亡率的最佳方法。尽管描述了许多能够保护肌细胞免受致命损伤的干预措施，但在临床领域应用这些干预措施的潜在希望仍然无法满足，部分原因是对心脏对压力的反应的综合了解。一个尚不清楚的特定区域是如何将肌膜膜跨导致的心肌应激转化为单个心肌水平的保护信号。我们实验室的长期目标是更好地理解负责心肌级别心脏保护信号传导的细胞和分子机制。该提案的目的是证明可以通过细胞骨架的途径发出信号传导，以增强对致命性缺血性损伤的肌细胞存活。局灶性粘附激酶（FAK）已被公认为是心脏和其他组织中细胞存活信号通路的关键介体。最近的数据表明，存在涉及FAK，细胞骨架和其他亚核信号传导蛋白的集成信号通路，这些信号通路可以被压力放大或刺激。特别是缺血/再灌注，热休克和/或膜受体刺激。该建议将检验以下假设：心肌应激直接或通过受体激活扩大了基于细胞骨架的信号级联反应，从而导致心肌细胞的存活率延长。该提案的具体目的表明：1）FAK的激活在对细胞外心肌应激的反应中起着核心作用； 2）基于细胞骨架的途径的激活通过AKT激活导致心脏保护； 3）途径的激活发生在完整的心脏中，可能为许多描述的心脏保护干预措施提供通用途径。通过应力激活的特定细胞存活蛋白将在使用重组腺病毒，生化和微观分析的一系列综合实验中进行评估，并对培养的心肌细胞进行了微观分析，并将在完整的心脏中确认使用隔离的灌注大鼠和小鼠的缺血性细胞死亡模型。这种生存/自适应途径的基本机制的表征将增强我们对不可逆伤害的理解，并可能导致急性心肌梗塞治疗的新的和创新的临床策略。