ANGIOTENSIN RECEPTOR AT1 IN VASCULAR CELL CONTROL

描述：(改编自申请人的摘要)很大一部分 人口受到高血压和心血管退行性疾病的困扰 所有这些因素的影响。因为上述患者的血浆AII水平通常是正常的。 在疾病状态下，受体调节可能存在异常 和/或细胞信号，其机制复杂且不完全 明白了。申请者将在培养中使用血管平滑肌细胞 I)定义负责激活的C-末端结构域 磷脂酶C；II)研究和确定串扰的机制 G蛋白偶联受体通过钙激活MAPK 钙调蛋白激酶；iii)鉴定负责 受体内化和脱敏机制；以及iv)下调 AT1信使核糖核酸的失稳调控。重点放在 主要的血管收缩、有丝分裂、肥大受体(AT1)和 胞质C-末端区域的调节功能。有待改进的技术 使用的包括受体抗体、AT1工程突变体、酵母两种 混合系统，以及特定的新抑制剂和检测技术。这个 使用细胞和分子工具的方法将提供重要的新 关于复杂受体调控和信号转导的信息，从而获得洞察力 各种血管疾病的潜在缺陷和治疗方法。

DESCRIPTION: (Adapted from the Applicant's Abstract) A large portion of the population is afflicted by the hypertensive and cardiovascular degenerative effects of AII. Because plasma levels of AII are often normal in the above disease states, abnormalities are likely to exist in receptor regulation and/or cell signaling, the mechanisms of which are complex and not fully understood. The applicant will use vascular smooth muscle cells in culture to i) define the C-terminal domain responsible for activation of phospholipase C; ii) investigate and identify the mechanisms of cross-talk by which the G-protein-coupled receptor activates MAPkinase via calcium calmodulin kinase; iii) identify receptor binding proteins responsible for receptor internalization and the mechanism of desensitization; and iv) down regulation of the AT1 mRNA by destabilization of the mRNA. The focus is on the dominant vasoconstrictor, mitogenic, hypertrophic receptor (AT1) and the regulatory function of the cytosolic C-terminal region. Techniques to be used include receptor antibodies, AT1 engineered mutant, the yeast two hybrid system, and specific new inhibitors and assay techniques. The approach using cellular and molecular tools will provide significant new information on complex receptor regulation and signaling and thus insights into potential defects in and therapy for various vascular diseases.