Modulation of Intracellular Signaling in Cardiac Hypertrophy

心脏肥大中细胞内信号传导的调节

• 批准号: 7298850
• 负责人: PHILIP J.S. STORK
• 金额: $ 18.14万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7298850
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Adult; Animal Model; Animals; Automobile Driving; Cardiac; Cardiac Myocytes; Cells; Complementary DNA; Development; Ectopic Expression; Enterobacteria phage P1 Cre recombinase; Equilibrium; Extracellular Signal Regulated Kinases; Genetic Models; Genetic Recombination; Goals; Green Fluorescent Proteins; Growth; Heart; Heart Hypertrophy; Hyperplasia; Hypertrophy; Hypoxia; Life; Mediating; Mitogen-Activated Protein Kinases; Modeling; Molecular Genetics; Monomeric GTP-Binding Proteins; Mus; Myocardial; Neonatal; Newborn Infant; Pathway interactions; Perinatal Hypoxia; Phosphotransferases; Program Research Project Grants; Proteins; Range; Ribosomal Protein S6 Kinase; Right Ventricular Hypertrophy; Right-On; Sheep; Signal Pathway; Signal Transduction; Site; Somatomedins; Stress; TSC2 gene; Testing; Transgenic Mice; Translations; cell growth; cell type; fetal; human FRAP1 protein; programs; promoter; response

A major hypothesis of this Program Project Grant is that intrauterine stresses can modify the program governing cell growth in adult life by dysregulating proliferative/hypertrophic signals within the heart. Understanding the signaling pathways that couple intrauterine stresses to cardiac growth are directly relevant to the overall goal of this PPG. We propose that selectively manipulating the proliferative and hypertrophic signals within the developing cardiomyocyte will provide an animal model of pathophysiological consequences of altered cardiac cell growth. We will establish genetic models in mice to test this hypothesis. The hypothesis to be tested in this proposal is that modifying hypertrophic and proliferative pathways converge to mediate the growth response in the heart. Studies by Kent Thornburg and co-workers have shown a requirement for extracellular signal-regulated kinase (ERK) and phosphoinositol-3 kinase (PI3-K) in the hyperplastic response of sheep myocardial cells to IGF. Recent studies suggest that PI3-K and ERK signals can also converge on hypertrophic signals via the mTOR pathway that regulates protein translation and growth. Importantly this pathway is also influenced by PI3-K and ERK signaling pathways. One of the major targets of mTOR action, the ribosomal p70 S6 kinase (S6K), is activated by both by PI3-K and ERK signaling pathways. We propose that activation of the mTOR pathway is sufficient for hypertrophy, and that both mTOR and ERKs are necessary for full hypertrophic response to developmental stresses. We predict that constitutive activation of the PI3-K/mTOR cascade is sufficient for cardiac hypertrophy and that both PI3-K/mTOR and ERK pathways are necessary for cardiac hypertrophy. This will be tested in three specific aims using genetically modified animal models of cardiac function.

该计划项目拨款的一个主要假设是子宫内压力可以修改计划 通过调节心脏内的增殖/肥大信号来控制成年后的细胞生长。 了解将子宫内应激与心脏生长耦合的信号通路是直接的 与本 PPG 的总体目标相关。我们建议有选择地操纵增殖和 发育中的心肌细胞内的肥大信号将提供病理生理学的动物模型 心肌细胞生长改变的后果。我们将在小鼠中建立遗传模型来测试这一点 假设。 该提案要测试的假设是改变肥大和增殖途径 集中调节心脏的生长反应。肯特·索恩伯格 (Kent Thornburg) 及其同事的研究表明 显示出细胞外信号调节激酶 (ERK) 和磷酸肌醇-3 激酶 (PI3-K) 的需要 绵羊心肌细胞对 IGF 的增生反应。最近的研究表明 PI3-K 和 ERK 信号还可以通过调节蛋白质翻译的 mTOR 途径汇聚到肥大信号上 和成长。重要的是，该通路还受到 PI3-K 和 ERK 信号通路的影响。中的一个 mTOR 作用的主要目标是核糖体 p70 S6 激酶 (S6K)，由 PI3-K 和 ERK 激活 信号通路。我们认为 mTOR 通路的激活足以导致肥大，并且 mTOR 和 ERK 都是对发育压力的全面肥大反应所必需的。 我们预测 PI3-K/mTOR 级联的组成型激活足以导致心脏肥大 PI3-K/mTOR 和 ERK 通路都是心脏肥大所必需的。这将在以下时间进行测试 使用转基因动物模型研究心脏功能的三个具体目标。