THE ROLE (S) OF PYK2 IN CARDIAC HYPERTROPHY

PYK2 在心脏肥大中的作用

• 批准号: 6056157
• 负责人: Allison Lorayne Bayer
• 金额: $ 3.24万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6056157
• 关键词: G protein; JUN kinase; biological signal transduction; calcium flux; cardiac myocytes; cell biology; endothelin; enzyme activity; flow cytometry; gene expression; laboratory rat; mitogen activated protein kinase; molecular biology; northern blottings; pathologic process; proline; protein kinase C; protein tyrosine kinase; receptor coupling; tissue /cell culture; ventricular hypertrophy; western blottings

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.

描述 尽管在治疗和对导致心力衰竭的发病机制的理解方面取得了进展，但所涉及的细胞和分子机制仍然很大程度上未知。左心室肥厚是与心力衰竭状态相关的常见特征，并且可能与收缩功能降低有关。因此，该提案的总体目标是确定导致心脏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 Ca2+ 流入和 PKC 激活的非受体酪氨酸激酶，被认为是一种重要的激酶，将 G 蛋白偶联受体的激活与其他细胞类型中的 ERK 和 JNK 的激活联系起来。本研究计划旨在检验钙依赖性非受体酪氨酸激酶 PYK2 在心肌细胞肥大表型的产生中发挥关键作用的假设。该提案的具体目标是 1) 评估心肌细胞中 PYK2 的表达 2) 确定 PYK2 在 MAP 激酶级联激活中的作用。了解与心脏肥大发展相关的受体和信号传导途径（例如基因表达的改变）可能会发现治疗心力衰竭的新治疗靶点。