ANGIOTENSIN RECEPTOR AT1 IN VASCULAR CELL CONTROL

描述：（改编自申请人的摘要） 受高血压和心血管退行性疾病困扰的人群 所有的影响。 由于血浆AII水平在上述情况下通常是正常的， 疾病状态下，受体调节可能存在异常 和/或细胞信号传导，其机制复杂且不完全 明白 申请人将使用培养的血管平滑肌细胞 i）定义负责激活的C-末端结构域， 磷脂酶C; ii）研究和鉴定串扰的机制 G蛋白偶联受体通过钙激活MAP激酶 钙调蛋白激酶; iii）鉴定负责 受体内化和脱敏机制;以及iv）降低 通过mRNA的不稳定来调节AT 1 mRNA。 重点是 主要的血管收缩、促有丝分裂、肥大受体（AT 1）和 胞质C-末端区域的调节功能。 技术被 使用的包括受体抗体、AT 1工程突变体、酵母两种 杂交系统和特定新抑制剂和分析技术。 的 使用细胞和分子工具的方法将提供重要的新 关于复杂受体调节和信号传导的信息， 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.