AT1 signaling in cardiac hypertrophy and apoptosis

AT1信号在心脏肥大和细胞凋亡中的作用

• 批准号: 7256939
• 负责人: PEIYONG ZHAI
• 金额: $ 5.8万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256939
• 关键词: Angiotensin II; Apoptosis; Autopsy; Cardiac; Cardiovascular system; Catheterization; Cause of Death; Cessation of life; Congestive Heart Failure; Coupling; Deformity; Echocardiography; Epidermal Growth Factor Receptor; G alpha q Protein; GTP-Binding Proteins; Genomics; Goals; Growth; Heart; Heart Hypertrophy; Heart failure; Heterotrimeric GTP-Binding Proteins; Immunoblotting; Laboratories; Measurement; Mediating; Mitogen-Activated Protein Kinases; Muscle Cells; Organ Weight; Patients; Play; Protein Overexpression; Protein Tyrosine Kinase; Proteomics; Receptor Signaling; Receptor, Angiotensin, Type 1; Role; Signal Transduction; Stream; System; Transactivation; Transgenic Mice; Tyrosine Phosphorylation; mutant; receptor; src-Family Kinases

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.

描述（由申请人提供）：血管紧张素II（ANG II）的心血管效应主要是通过ANG II型1受体（AT1）的信号传导介导的。了解AT1引起心脏肥大和心力衰竭的信号传导机制极为重要。有大量证据表明，AT1通过G蛋白依赖性和非依赖性机制起作用，并反式激活表皮生长因子受体（EGFR）。因此，这项研究的目的是评估这些信号传导机制在调节心脏肥大和凋亡中。该项目有2个具体目标。在AIM 1中，将确定是否刺激心脏肥大，而在过表达缺乏GAQ偶联的AT1突变体的转基因小鼠中凋亡降低。在AIM 2中，将确定是否废除了心脏肥大，而在过表达AT1突变体的转基因小鼠中凋亡被激活，该突变体无法激活EGFR。将对器官重量，超声心动图，LV导管插入术，组织学分析的验尸测量，以表征心脏肥大，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向下流信号传导机制。