Angiotensin Receptor AT1 in Cardiovascular Cell Control.

这项申请建议继续、扩展和增加新的角度来研究 血管紧张素II在心肌细胞重塑中的作用及其信号机制。它基于以下新发现： 表皮受体与血管紧张素Ⅱ1型受体在细胞外信号反应中的相互作用 ERK，以及几种非受体酪氨酸激酶和酪氨酸磷酸酶的参与 它们包括Janus激酶(JAK2)、富含脯氨酸的酪氨酸激酶(PYK2)、含有磷酸酶-2的SH2和- 1(SHP-2和SHP-1)蛋白激酶C(尤其是PKC-Delta)。它们与其他生物形成了一个巨大的复合体 咖啡因蛋白GAB1和小G蛋白Rap1，它们负责激活cJun NH2- KK(JNK)，细胞迁移，并使这些细胞对他汀类药物的有利作用作出反应。 我们建议为研究AT1延长表达的信号机制增加一个新的角度 在2点之前。 根据我们的初步发现，心肌肥厚之前会出现压力超负荷，这会导致 血管紧张素II 2型受体(AT2)的表达在长期增加之前显著增加 1受体(AT1)的表达，我们将评估压力超负荷导致心脏 肥大和AT1的表达由AT2控制，AT2激活转录因子早幼粒细胞 锌指蛋白PLZF。这些研究将为心血管疾病的发病机制提供重要的见解。 重塑，并将有助于开发特定的治疗措施和预防方法 应对因心血管重塑引起的病态和致命性疾病。

This application proposes to continue, extend and add new angles to the investigation of the role of angiotensin II (Ang II) in myocyte remodeling and signaling mechanisms for it. It is based on new findings of cross-talk between epidermal receptor and the Ang II type 1 (AT1) receptor in extracellular signal-response kinase (ERK), as well as involvement of several non-receptor tyrosine kinases and tyrosine phosphatases which include Janus kinase (JAK2), proline rich tyrosine kinase (PYK2), SH2 containing phosphatase-2 and - 1 (SHP-2 and SHP-1) protein kinases C (particularly PKC-delta). They form a large complex with other ¿caffold proteins Gab1, and small G-protein Rap1, and they are responsible for activation of cJun NH2- kinase (JNK), cellular migration and make these cells responsive to favorable action of statins. We propose to add a new angle to studies on signaling mechanism regulating prolonged expressionof AT1 byAT2. Based on our preliminary finding that cardiac hypertrophy is preceded by pressure overload, which induces a marked increase in the angiotensin II type 2 receptor (AT2) expression before long term increase in the type 1 receptor (AT1) expression, we will evaluate the hypothesis that pressure overload induced cardiac hypertrophy and AT1 expression is controlled by AT2, which activate the transcription factor promyelocytic zinc finger protein PLZF. These studies will provide important insights into the mechanism of cardiovascular remodeling and will be useful for developing specific therapeutic remedies and preventative approaches to cope with morbid and mortal diseases due to cardiovascular remodeling.