Modulation of Intracellular Signaling in Cardiac Hypertrophy

该计划项目赠款的一个主要假设是，宫内压力可以修改该计划 通过失调心脏内的增殖/肥大信号来控制成年生命中的细胞生长。 了解宫内压力与心脏发育相关的信号通路是直接的 与这个PPG的总体目标相关。我们建议有选择地操纵增殖性和 发育中的心肌细胞内的肥大信号将提供一种病理生理的动物模型 心脏细胞生长改变的后果。我们将在老鼠身上建立遗传模型来测试这一点 假设。 这项提议中要检验的假设是，修改肥大和增殖途径 汇聚于心，调和成长反应。肯特·索恩伯格和他的同事们的研究 显示需要细胞外信号调节激酶(ERK)和磷酸肌醇-3激酶(PI3-K)。 绵羊心肌细胞对胰岛素样生长因子的增殖反应。最近的研究表明，PI3-K和ERK 信号也可以通过调节蛋白质翻译的mTOR通路汇聚成肥大信号 和增长。重要的是，该通路还受PI3-K和ERK信号通路的影响。其中一个 MTOR作用的主要靶点是核糖体p70 S6激酶(S6K)，它被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厚，并且 MTOR和ERKs都是对发育应激做出全面肥大反应所必需的。 我们预测PI3-K/mTOR级联的结构性激活足以导致心肌肥厚 PI3-K/mTOR和ERK通路在心肌肥厚中都是必需的。这将在 使用转基因的心脏功能动物模型有三个具体目标。

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.