Rassf1A signaling in cardiac hypertrophy, fibrosis and failure

描述(申请人提供)：尽管最近医学治疗取得了进展，但心力衰竭仍是西方国家最常见的死亡原因之一。了解调节心肌生长和死亡的分子机制是至关重要的，并可能导致更好的心力衰竭治疗。该实验室一直在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方面发挥着重要作用。尽管这种酶在心脏对高血压和心力衰竭的反应是被激活的，但Mst1在心脏被激活的分子机制还不是很清楚。本项目的目的是研究Mst1的调节因子，即Ras相关结构域家族1、异构体A(RassfIA)和K-RAS，在介导Mst1的激活、心肌细胞的生长和死亡以及由此对心脏功能的影响中所起的作用。基因改变的RassfIA和K-RAS小鼠将受到横断性主动脉收缩，并被用来研究RassfIA在心肌肥厚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由此产生的心脏表型。RassfIA可以调节心肌纤维化的可能性也将被讨论，重点是作为一种潜在的介体的核因子-kB。培养的心肌细胞和成纤维细胞将作为易于处理的系统，以允许检查涉及RassfIA和Mst1的信号通路。这项工作还将寻求评估K-RAS作为心脏这一信号通路的上游激活剂。本研究获得的知识将进一步阐明Mst1在体内的调节机制，并将有助于开发更好的心力衰竭治疗方法。

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.