Rassf1A signaling in cardiac hypertrophy, fibrosis and failure

Rassf1A 信号在心脏肥大、纤维化和衰竭中的作用

• 批准号: 7806875
• 负责人: Dominic P Del Re
• 金额: $ 4.88万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-27 至 2011-10-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7806875
• 关键词: Ablation; Address; Apoptosis; Binding; Biochemical; Cardiac; Cardiac Myocytes; Cause of Death; Cessation of life; Chronic; Country; Data; Development; Echocardiography; Enzymes; Failure; Family; Fibroblasts; Fibrosis; Functional disorder; Growth; Heart; Heart Hypertrophy; Heart failure; Histology; Hypertension; Injury; Investigation; Knockout Mice; Knowledge; Laboratories; Lead; Measurement; Mediating; Mediator of activation protein; Medical; Molecular; Mus; Muscle Cells; Myocardial Infarction; Myocardium; Organ; Phenotype; Phosphotransferases; Play; Production; Protein Isoforms; Regulation; Reperfusion Injury; Role; Signal Pathway; Signal Transduction; Sterility; Stress; System; Testing; Transgenic Mice; Tumor Suppressor Proteins; Work; base; cell growth; cell type; constriction; cytokine; heart function; hemodynamics; improved; in vivo; mouse model; mutant; pressure; prevent; promoter; response

DESCRIPTION (provided by applicant): Despite recent progress in medical therapy, heart failure is one of the most common causes of death in western countries. Understanding the molecular mechanism mediating growth and death of cardiac muscle is fundamentally important and can potentially lead to better medical treatment for heart failure. This laboratory has been working on an enzyme termed mammalian sterile 20-like kinase 1 (Mst1) which plays an essential role in regulating growth and death of cardiac myocytes. Although this enzyme is activated in the heart in response to high blood pressure and during heart failure, the molecular mechanism by which Mst1 is activated in the heart is not well understood. The aims of this project are to investigate the role of putative regulators of Mst1, termed Ras-association domain family 1, isoform A (RassfIA) and K-Ras, in mediating the activation of Mst1, growth and death of cardiac myocytes, and the resulting impact on heart function. Genetically altered RassfIA and K-Ras mice will be subjected to transverse aortic constriction and used to study the role of RassfIA in the development of cardiac hypertrophy and heart failure. Echocardiography, hemodynamic analysis, post-mortem organ measurements, histology and biochemical analysis will all be used to determine and compare resulting cardiac phenotypes. The possibility that RassfIA can modulate cardiac fibrosis will also be addressed with a focus on NF-KB as a potential mediator. Cultured cardiac myocytes and fibroblasts will serve as tractable systems to allow for the examination of signaling pathways involving RassfIA and Mst1. This work will also seek to evaluate K-Ras as an upstream activator of this signaling pathway in the heart. The knowledge obtained from this investigation will further elucidate the mechanism of Mst1 regulation in vivo and should be useful for the development of better treatment for heart failure.

描述（由申请人提供）：尽管最近医学治疗取得了进展，但心力衰竭仍然是西方国家最常见的死亡原因之一。了解介导心肌生长和死亡的分子机制至关重要，并且有可能为心力衰竭提供更好的医疗方法。该实验室一直致力于研究一种名为哺乳动物不育20样激酶1（Mst1）的酶，它在调节心肌细胞的生长和死亡中发挥着重要作用。尽管这种酶在心脏中因高血压和心力衰竭而被激活，但 Mst1 在心脏中被激活的分子机制尚不清楚。该项目的目的是研究 Mst1 的假定调节因子（称为 Ras 关联域家族 1、异构体 A (RassfIA) 和 K-Ras）在介导 Mst1 激活、心肌细胞生长和死亡以及心肌细胞生长和死亡中的作用。从而对心脏功能产生影响。基因改造的 RassfIA 和 K-Ras 小鼠将接受横向主动脉缩窄，并用于研究 RassfIA 在心脏肥大和心力衰竭发展中的作用。超声心动图、血流动力学分析、死后器官测量、组织学和生化分析都将用于确定和比较所得的心脏表型。还将讨论 RassfIA 调节心脏纤维化的可能性，重点关注 NF-KB 作为潜在介质。培养的心肌细胞和成纤维细胞将作为易于处理的系统，用于检查涉及 RassfIA 和 Mst1 的信号通路。这项工作还将寻求评估 K-Ras 作为心脏中该信号通路的上游激活剂。从这项研究中获得的知识将进一步阐明 Mst1 体内调节机制，并且应该有助于开发更好的心力衰竭治疗方法。