THE ROLE (S) OF PYK2 IN CARDIAC HYPERTROPHY

尽管在治疗和了解导致心力衰竭的发病机制方面取得了进展，但所涉及的细胞和分子机制在很大程度上仍不清楚。左心室肥厚是与心力衰竭状态相关的常见特征，可能与收缩功能降低有关。因此，这项提议的总体目标是确定导致心肌肥大的信号转导途径。一些研究人员已经证明，用肥大激动剂处理培养的NRVM会导致MAP激酶家族的激活，包括ERK1/2、JNK1/2和p38。PYK2是一种由钙离子内流和PKC激活的非受体酪氨酸激酶，是连接G蛋白偶联受体激活和ERK和JNK在其他类型细胞中激活的重要激酶。本研究旨在验证一种假说，即钙依赖的非受体酪氨酸激酶PYK2在心肌细胞肥大表型的产生中起关键作用。本研究的具体目的是：1)评价PYK2在心肌细胞中的表达；2)确定PYK2在MAP激活级联反应中的作用(S)。了解与心肌肥厚发展相关的受体和信号通路，如基因表达的变化，可能会导致发现治疗心力衰竭的新靶点。

DESCRIPTION Despite advancement in the treatment and understanding of the pathogenesis leading to heart failure, the cellular and molecular mechanisms involved are still largely unknown. Left ventricular hypertrophy is a common feature associated with the heart failure state, and may be associated with reduced contractile function. Therefore, the overall goal of this proposal is to determine the signal transduction pathways leading to cardiac hypertrophy. Several researchers have demonstrated that treatment of cultured NRVM with hypertrophic agonists leads to activation of the family of MAP kinases including ERK1/2, JNK1/2, and p38. PYK2, a non-receptor tyrosine kinase activated by Ca2+ influx and PKC, has been implicated as an important kinase linking the activation of G protein-coupled receptors to the activation of ERK and JNK in other cell types. The present research proposal is designed to test the hypothesis that the calcium-dependent non-receptor tyrosine kinase PYK2 plays a critical role in the generation of the hypertrophic phenotype in cardiac myocytes. The Specific Aims of this proposal are 1) to evaluate the expression of PYK2 in cardiac myocytes 2) to determine the role(s) of PYK2 in activation of the MAP kinase cascades. Understanding the receptors and signaling pathways associated with the development of cardiac hypertrophy, such as alterations in gene expression, may result in the discovery of novel therapeutic targets for the treatment of heart failure.