Angiotensin Receptor AT1 in Vascular Cell Control.

描述(逐字摘自申请)：多肽激素血管紧张素II (血管紧张素转换酶)导致各种心血管疾病，如高血压， 动脉粥样硬化和心力衰竭。安吉里的促生长活动 1型(AT1)受体参与心血管疾病的进展 改建。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其促生长信号 (PYK2、Src、JAK和EGF受体)。我们已经报告过这种激活 Angli对EGF受体(EGFR)的激活是ERK和 血管紧张素转换酶诱导c-Fos和蛋白合成 培养的VSMC。因此，EGFR的反式激活可能在 血管紧张素转换酶介导血管重塑。几种机制牵涉到上游 酪氨酸激酶、活性氧(ROS)和金属蛋白酶依赖性 建议生成EGFR配体进行反式激活。然而，a 在Angii/AT1的机制方面，我们的知识仍然存在巨大的空白 激活EGFR。此外，目前还不清楚其他信号，如 血管紧张素转换酶抑制p38和JNK蛋白的激活 反式激活，如果它们受其他酪氨酸激酶调节，或者如果一个 酪氨酸磷酸酶如SHP-2参与其中。因此，我们将评估 假设酪氨酸激酶(PYK2和JAK2)。酪氨酸磷酸酶 SHP-2。罗斯。而金属蛋白酶ADAM调节EGFR和/或MAP的激活 血管紧张素转换酶在VSMC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 血管紧张素转换酶(PYK2、JAK2、ROS、金属蛋白酶)的作用机制 酪氨酸激酶在Angli激活p38和JNK中的作用 研究SHP-2在PYK2调控中的作用；4)研究 SHP-2在血管紧张素Ⅱ调节MAP激酶中的作用。这些研究将会瓦解 血管紧张素转换酶等血管营养因子的最初关键机制 调节血管重塑。此外，澄清不可缺少的 肥大和增生性信号与肿瘤的鉴别 关键的酶(激酶和/或磷酸酶)将提供潜在的治疗作用 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.