GP130/RETINOID SIGNALS IN HYPERTROPHY AND CARDIOMYOPATHY

心肌肥厚是机体最重要的适应性反应之一 在心脏功能障碍的发生中起着关键作用 在向心力衰竭转变的过程中。 虽然准确的信号 这些途径协调了体内的特定特征， 肥大反应是未知，已经取得了很大的进展， 对信号通路进行分子解剖， 可能调节体外培养的新生大鼠心脏细胞的肥大。 在过去五年中，设计了一项实验性战略， 首先在充分表征的 培养的心肌细胞模型系统，然后进行严格的 这些分子在体内模型系统中的作用的评估 成年小鼠心脏的肥大。 先前的研究 建立了这个小鼠模型作为一个有效的系统， 包括人类在内的大型哺乳动物的肥大。 生理技术已经与转基因和基因技术相结合， 确定具体目标之间因果关系的目标战略 通路中的组分和定义的分子的起始， 肥大的形态学和生理学特征。 我们当前计划的中心主题是批判性地评估 候选信号通路在激活不同的 在体内心脏肥大和扩张型心肌病的特点， 成人心肌 最近的研究已经确定了gp 130 和维甲酸依赖的信号通路在积极和消极的 控制体外测定系统中的肥大反应。 最近，心肌营养素-1和gp 130依赖性途径已被证实是一种新的心肌营养素。 显示促进心肌细胞存活（1）并阻断 心肌细胞凋亡通过MAP激酶依赖途径（2）。 在 此外，最近的研究支持gp 130和 类维生素A信号通路在心脏生长和/或肥大中的作用 体内竞赛。 该项目的主要目标是严格 评估gp 130和类维生素A信号通路在阳性 和负调控的不同表型特征的体内 心脏肥大，并随后探讨这些作用 偏心性表型特征激活的途径 在扩张的情况下观察到的肥大和功能障碍 心肌病 中央方法将利用以下组合： 微型生理技术和各种方法， 在成年小鼠心脏中设计获得和丧失功能的突变。 确定gp 130和RXR α在活化中的作用 或者说，在一个特定的环境中， 心肌病最终可能导致新的 对介导转变的决定因素的分子见解 从心脏肥大到心力衰竭

Cardiac hypertrophy is one of the most important adaptive responses of the heart and plays a critical role in the onset of cardiac dysfunction during the transition to heart failure. Although the precise signaling pathways which orchestrate specific features of the in vivo hypertrophic response are unknown, a great deal of progress has been made toward the molecular dissection of the signaling pathways which might regulate in vitro hypertrophy in cultured neonatal rat heart cells. In the past five years, an experimental strategy has been designed to first identify candidate signaling molecules in a well-characterized cultured myocardial cell model system, followed by a rigorous assessment of the role of these molecules in an in vivo model system of hypertrophy in the adult mouse heart. Previous studies have established this mouse model as a valid system with fidelity to hypertrophy in larger mammalian species, including man. Miniaturized physiological technology has been coupled with transgenic and gene targeting strategies to exact cause-effect relationships between specific components in the pathway and the onset of defined molecular, morphological, and physiological features of hypertrophy. The central theme of our current Program is to critically evaluate the role of candidate signaling pathways in the activation of distinct features of in vivo cardiac hypertrophy and dilated cardiomyopathy in adult myocardium. Recent studies have defined a role for both gp130 and retinoid-dependent signaling pathways in the positive and negative control of the hypertrophic response in the in vitro assay system. Recently, cardiotrophin-1 and gp130 dependent pathways have been shown to promote cardiac myocyte survival (1) and to block cardiomyocyte apoptosis via MAP kinase dependent pathways (2). In addition, recent studies support an important role for both gp130 and retinoid signaling pathways in cardiac growth and/or hypertrophy in the in vivo contest. The major objective of this Project is to rigorously assess the role of gp130 and retinoid signaling pathways in the positive and negative regulation of distinct phenotypic features of in vivo cardiac hypertrophy, and subsequently to explore the role of these pathways in the activation of phenotypic feature of eccentric hypertrophy and dysfunction seen in the setting of dilated cardiomyopathy. The central approach will utilize a combination of miniaturized physiological technology and a variety of approaches to engineer gain and loss of function mutations in the adult mouse heart. The identification of a role for gp130 and RXRalpha in the activation or suppression (respectively) of hypertrophy in the setting of delated cardiomyopathy could ultimately lead to the identification of new molecular insights into the determinants that mediate the transition from cardiac hypertrophy to heart failure.