Modulation of Intracellular Signaling in Cardiac Hypertrophy

该项目资助的一个主要假设是子宫内压力可以改变该项目 通过心脏内的增殖/肥大信号失调来控制成年期的细胞生长。 了解子宫内应激与心脏生长之间的信号通路， 与本PPG的总体目标相关。我们建议，选择性地操纵增殖和 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， 改变心脏细胞生长的后果。我们将在小鼠中建立遗传模型来测试这一点 假说. 在这项提议中要检验的假设是，改变肥大和增殖途径 汇聚在一起来调节心脏的生长反应。肯特·索恩伯格和同事的研究表明， 显示细胞外信号调节激酶（ERK）和磷酸肌醇-3激酶（PI 3-K）在 绵羊心肌细胞对IGF的增生反应。最近的研究表明，PI 3-K和ERK 信号也可以通过调节蛋白质翻译的mTOR途径聚集在肥大信号上 和增长重要的是，该通路还受PI 3-K和ERK信号通路的影响。之一 mTOR作用的主要靶点是核糖体p70 S6激酶（S6 K），它被PI 3-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， mTOR和ERK都是对发育应激的完全肥大反应所必需的。 我们预测PI 3-K/mTOR级联反应的组成性激活足以导致心肌肥厚 PI 3-K/mTOR和ERK通路在心肌肥大中均是必需的。这将在 三个具体的目的是使用转基因动物模型的心脏功能。

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.