GG MEDIATED PATHWAYS AND VENTRICULAR HYPE

GG 介导的通路和心室过度兴奋

• 批准号: 2415507
• 负责人: Shahab A Akhter
• 金额: $ 2.49万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2415507
• 关键词: alpha adrenergic receptor; biological signal transduction; genetically modified animals; guanine nucleotide binding protein; laboratory mouse; phospholipase C; protein structure function; pulmonary artery; ventricular hypertrophy

Myocardial hypertrophy is an adaptive response to pressure overload and represents an initial step in the pathogenesis of many cardiac diseases which ultimately progress to ventricular failure. Biochemical mediators which initiate the hypertrophic response are poorly understood. In vitro studies with neonatal myocytes have demonstrated that activation of membrane-bound receptors which couple to the heterotrimeric guanine nucleotide-binding (G) protein, Gq, results in cellular hypertrophy. Stimulation of the alpha1 adrenergic receptor (AR) is the most studied Gq- mediated pathway which induces both myocyte hypertrophy in vitro and nuclear transcription factors associated with hypertrophy. The purpose of this study is to characterize the role of myocardial Gq-mediated pathways in ventricular hypertrophy using an in vivo model. Several lines of transgenic mice will be created with cardiac-specific expression of either the third intracellular loop region of the alpha1B-AR o the carboxyl terminus of the Gq-alpha subunit. These two peptides have been shown to inhibit phospholipase C signaling via Gq in mammalian cells in culture. Morphological changes will be determined in transgenic animals compared to controls using heart to body weight ratios and determination of ventricular myocyte cross-sectional area. Biochemical mediators of Gq- activation will also be studied. Transgenic and control mice will then undergo pulmonary artery (PA) banding which produces right ventricular pressure overload and subsequent hypertrophy. Biochemical, morphological, and histological characterization of the myocardium will be performed at various times after PA banding for both groups. This will define the importance of Gq signaling in the initiation of the hypertrophic response.

心肌肥大是对压力超负荷和 代表许多心脏病的发病机理的第一步 最终发展为心室衰竭。生化介体 引发肥厚反应的理解很少。体外 新生儿心肌细胞的研究表明，激活 膜结合的受体，夫妇与异三聚体鸟嘌呤 核苷酸结合（G）蛋白GQ导致细胞肥大。 刺激α1肾上腺素能受体（AR）是研究最多的GQ- 介导的途径在体外诱导肌细胞肥大和 与肥大相关的核转录因子。目的 这项研究是为了表征心肌GQ介导的途径的作用 在心室肥大中使用体内模型。几行 转基因小鼠将以任何任一的心脏特异性表达创建 羧基的第三个细胞内环区域 GQ-Alpha亚基的末端。这两个肽已被证明 通过培养物中哺乳动物细胞中的GQ抑制磷脂酶C信号传导。 与转基因动物相比，将确定形态学变化 使用心脏与体重比的控制和确定 心室心肌横截面区域。 GQ-的生化介体 还将研究激活。 然后，转基因和对照小鼠将 经历肺动脉（PA）带来的右心室 压力超负荷和随后的肥大。 生化，形态学， 心肌的组织学表征将在 两组的PA带后的不同时间。这将定义 GQ信号在肥厚反应的启动中的重要性。