THE ROLE (S) OF PYK2 IN CARDIAC HYPERTROPHY

PYK2 在心脏肥大中的作用

• 批准号: 6351455
• 负责人: Allison Lorayne Bayer
• 金额: $ 4.02万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6351455
• 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; 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.

尽管在治疗和理解导致心力衰竭的病理方面进行了描述，但涉及的细胞和分子机制仍在很大程度上未知。左心室肥大是与心力衰竭相关的共同特征，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。一些研究人员表明，用肥大性激动剂对培养的NRVM进行处理会导致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，已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。本研究建议旨在检验以下假设：依赖钙的非受体酪氨酸激酶PYK2在心肌细胞中肥大表型的产生中起着至关重要的作用。该提案的具体目的是1）评估心肌细胞中PYK2的表达2）确定PYK2在MAP激酶级联反应激活中的作用。了解与心脏肥大发展相关的受体和信号通路，例如基因表达的改变，可能会导致发现用于治疗心力衰竭的新型治疗靶标。