ErbB Activation via a Metalloprotease by Angiotensin II

血管紧张素 II 通过金属蛋白酶激活 ErbB

• 批准号: 7188543
• 负责人: SATORU EGUCHI
• 金额: $ 32.11万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7188543
• 关键词: Angiotensin II; Atherosclerosis; Blood Vessels; Cardiovascular Diseases; Cytoplasmic Tail; Development; Disease; Epidermal Growth Factor Receptor; Family; GTP-Binding Proteins; Hyperplasia; Hypertension; Hypertrophy; Injury; Ligands; Mediating; Metalloproteases; Molecular; Play; Production; Protein Tyrosine Kinase; Role; Second Messenger Systems; Signal Transduction; Smooth Muscle Myocytes; Testing; Transactivation; Vascular remodeling; design; migration; novel; receptor; restenosis; second messenger; vascular smooth muscle cell migration

DESCRIPTION (provided by applicant): Angiotensin II (Angll) and its G protein-coupled AT1 receptor play critical roles in mediating cardiovascular diseases such as hypertension, atherosclerosis, and restenosis after vascular injury. It is widely believed that Angll promotes these diseases by inducing vascular remodeling that involves hypertrophy, hyperplasia, and migration of vascular smooth muscle cells (VSMCs). It has been shown that transactivation of an ErbB family receptor, EGF receptor (ErbB1/EGFR), is essential for VSMC hypertrophy and migration by Angll. However, the precise signal transduction mechanism by which Angll transactivates EGFR/ErbB1 and whether other ErbBs are also required for Angll function remains unclear. Recent studies suggest an involvement of a metalloprotease-dependent ErbB family ligand production in the transactivation. Thus, our central hypothesis is that an AT1-derived second messenger promotes activation of ADAM metalloprotease leading to ErbB receptors transactivation and subsequent remodeling in VSMCs. Our past and current preliminary studies strongly support our central hypothesis. Therefore, the specific aims of this application are designed to identify the signaling mechanism(s) and functional significance of the metalloprotease/ErbB activation by Angll in VSMCs. The specific aims of the study are: Aim 1. To test the hypothesis that G protein and second messengers are involved in metalloprotease activation through the AT1 receptor. Aim 2. To test the hypothesis that ADAM metalloprotease is activated by a mechanism involving ADAM cytoplasmic tail and a cytosolic tyrosine kinase. Aim 3. To test the hypothesis that several ErbB ligands are produced by Angll and mediate Angll-induced transactivation of ErbB receptors. Aim 4. To test the hypothesis that the transactivation of ErbB receptors is required for hypertrophy and migration of VSMCs induced by Angll. Accomplishment of these specific aims will not only give us a better understanding of the critical molecular mechanism underlying vascular remodeling stimulated by Angll but will also contribute to development of novel treatment strategies toward cardiovascular diseases.

描述（申请人提供）：血管紧张素II（AngII）及其G蛋白偶联AT1受体在介导心血管疾病如高血压、动脉粥样硬化和血管损伤后的再狭窄中发挥关键作用。人们普遍认为AngII通过诱导血管重塑来促进这些疾病，血管重塑涉及血管平滑肌细胞（VSMC）的肥大、增生和迁移。研究表明，ErbB 家族受体、EGF 受体 (ErbB1/EGFR) 的反式激活对于 AngII 导致的 VSMC 肥大和迁移至关重要。然而，AngII反式激活EGFR/ErbB1的精确信号转导机制以及AngII功能是否也需要其他ErbB仍不清楚。最近的研究表明金属蛋白酶依赖性 ErbB 家族配体的产生参与了反式激活。因此，我们的中心假设是 AT1 衍生的第二信使促进 ADAM 金属蛋白酶的激活，导致 ErbB 受体反式激活和随后的 VSMC 重塑。我们过去和当前的初步研究有力地支持了我们的中心假设。因此，本申请的具体目标是确定 VSMC 中 AngII 激活金属蛋白酶/ErbB 的信号传导机制和功能意义。该研究的具体目的是： 目的 1. 检验 G 蛋白和第二信使通过 AT1 受体参与金属蛋白酶激活的假设。目标 2. 检验 ADAM 金属蛋白酶通过涉及 ADAM 胞质尾部和胞质酪氨酸激酶的机制激活的假设。目标 3. 检验以下假设：若干 ErbB 配体由 AngII 产生并介导 AngII 诱导的 ErbB 受体反式激活。目的 4. 检验 ErbB 受体反式激活是 AngII 诱导的 VSMC 肥大和迁移所必需的假设。这些具体目标的实现不仅将使我们更好地了解AngII刺激血管重塑的关键分子机制，而且还将有助于开发针对心血管疾病的新治疗策略。