Angiotensin Receptor AT1 in Vascular Cell Control.

描述（来自申请的逐字）：肽激素血管紧张素II （AngII）导致各种心血管疾病，例如高血压， 动脉粥样硬化和心力衰竭。AngII的促生长活性 1型（AT 1）受体参与心血管疾病的进展 重塑在血管平滑肌细胞（VSMC）中，AngII被认为是 通过激活酪氨酸激酶传递促生长信号 (PYK2、Src、JAK和EGF受体）。我们已经报道过反式激活 EGF受体（EGFR）的Angi是必不可少的激活ERK和 p70 S6激酶，以及随后的c-Fos诱导和AngII的蛋白质合成。 培养的VSMC。因此，EGFR反式激活可能在以下方面发挥核心作用： AngII介导的血管重构。涉及上游的几种机制 酪氨酸激酶、活性氧（ROS）和金属蛋白酶依赖性 EGFR配体的产生被提出用于反式激活。但 在AngII/AT 1的作用机制方面，我们的知识仍然存在巨大的空白， 激活EGFR。此外，尚不清楚是否有其他信号， AngII对p38和JNK MAP激酶的激活受 反式激活，如果它们由其他酪氨酸激酶调节，或者如果它们是 酪氨酸磷酸酶如SHP-2也参与其中。因此，我们将评估 酪氨酸激酶（PYK 2和JAK 2）。酪氨酸磷酸酶 SHP-2。罗斯并且金属蛋白酶ADAM调节EGFR和/或MAP的活化 血管紧张素Ⅱ在血管平滑肌细胞中的表达。本申请的具体目的是：1） 研究以下因素在EGFR反式激活中的作用 通过AngII（PYK 2，JAK 2，ROS，金属蛋白酶）的机制; 2）研究 酪氨酸激酶参与AnglI对p38和JNK的激活; 3） 研究SHP-2在PYK 2调节中的作用; 4）研究 SHP-2在AngII调节MAP激酶中的作用这些研究将揭开 血管营养因子如Angil 调节血管重塑。此外，澄清不可或缺的 肥大和增生信号结合识别 关键酶（激酶和/或磷酸酶）将提供潜在的治疗 心血管疾病的靶点。

DESCRIPTION (Verbatim from the application): The peptide hormone angiotensin II (AngII) contributes to various cardiovascular diseases such as hypertension, atherosclerosis, and heart failure. The growth promoting activity of the AngII type-1 (AT1) receptor is implicated in the progression of cardiovascular remodeling. In vascular smooth muscle cells (VSMC), AngII is believed to transmit its growth-promoting signal through activation of tyrosine kinases (PYK2, Src, JAK, and EGF receptor). We have reported that the transactivation of the EGF receptor (EGFR) by Angli is essential for the activation of ERK and p70 S6 kinase, and subsequent c-Fos induction and protein synthesis by AngII in cultured VSMC. Thus, the EGFR transactivation could play a central role in AngII mediated vascular remodeling. Several mechanisms implicating an upstream tyrosine kinase, reactive oxygen species (ROS) and a metalloprotease-dependent generation of an EGFR ligand are proposed for the transactivation. However, a huge void remains in our knowledge in terms of the mechanism by which AngII/AT1 activates the EGFR. Also, it is not clear whether other signals such as activation of p38 and JNK MAP kinases by AngII are under control of transactivation, if they are regulated by other tyrosine kinases, or if a tyrosine phosphatase such as SHP-2 is involved. Thus, we will evaluate the hypothesis that the tyrosine kinases (PYK2 and JAK2). the tyrosine phosphatase SHP-2. ROS. and the metalloprotease ADAM regulate activation of EGFR and/or MAP kinases by AngII in VSMC. The specific aims of this application are 1) to investigate the roles of the following factors in the EGFR transactivation mechanisms by AngII (PYK2, JAK2, ROS, metalloprotease); 2) to investigate the involvement of the tyrosine kinases in activation of p38 and JNK by AnglI; 3) to investigate the role of SHP-2 in regulation of PYK2; 4) to investigate the role of SHP-2 in regulation of MAP kinases by AngII. These studies will unravel the initial key mechanism by which vasculotrophic factors such as Angil regulate vascular remodeling. Moreover, the clarification of the indispensable hypertrophic and hyperplastic signals in combination with the identification of key enzymes (kinases and/or phosphatases) will provide potential therapeutic targets in cardiovascular diseases.