AT1 signaling in cardiac hypertrophy and apoptosis

描述（由申请人提供）：血管紧张素II（Ang II）的心血管效应主要通过Ang II 1型受体（AT 1）的信号传导介导。了解AT1导致心脏肥大和心力衰竭的信号机制非常重要。有相当多的证据表明，AT 1通过G蛋白依赖性和非依赖性机制发挥作用，并反式激活表皮生长因子受体（EGFR）。因此，本研究的目的是评估这些信号转导机制在调节心肌肥厚和凋亡。该项目有两个具体目标。在目的1中，将确定在过表达缺乏Gaq偶联的AT 1突变体的转基因小鼠中是否刺激心脏肥大同时减少细胞凋亡。在目的2中，将确定在过表达不能激活EGFR的AT 1突变体的转基因小鼠中，心脏肥大是否被消除，同时细胞凋亡是否被激活。死后测量器官重量、超声心动图、LV导管插入术、组织学分析将用于表征心脏肥大、细胞凋亡和功能。免疫印迹、免疫染色、基因组和蛋白质组学分析将用于揭示下游信号传导机制。

DESCRIPTION (provided by applicant): The cardiovascular effects of angiotensin II (Ang II) are primarily mediated via signaling through Ang II type 1 receptor (AT1). Understanding the signaling mechanisms by which AT1 causes cardiac hypertrophy and heart failure is extremely important. There is considerable evidence that AT1 acts through both G protein-dependent and -independent mechanisms and transactivates epidermal growth factor receptor (EGFR). Therefore the goal of this study is to evaluate these signaling mechanisms in modulating cardiac hypertropy and apoptosis. There are 2 specific aims of this project. In aim 1, it will be determined if cardiac hypertrophy is stimulated while apoptosis is reduced in transgenic mice overexpressing an AT1 mutant lacking Gaq coupling. In aim 2, it will be determined if cardiac hypertrophy is abolished while apoptosis is activated in transgenic mice overexpressing AT1 mutant which cannot activate EGFR. Postmortem measurements of organ weight, echocardiography, LV catheterization, histological analyses will be appllied to characterize cardiac hypertrophy, apoptosis, and function. Immunoblotting, immunostaining, genomic and proteomic analyses will be used to reveal the down stream signaling mechanisms.