Rassf1A signaling in cardiac hypertrophy, fibrosis and failure

描述（由申请人提供）：尽管医学治疗最近取得了进展，但心力衰竭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，并可能导致更好的心力衰竭药物治疗。该实验室一直在研究一种名为哺乳动物无菌20样激酶1（Mst 1）的酶，该酶在调节心肌细胞的生长和死亡中起着重要作用。虽然这种酶在心脏中响应于高血压和心力衰竭而被激活，但Mst 1在心脏中被激活的分子机制尚不清楚。本项目的目的是研究Mst 1的推定调节因子，称为Ras-相关结构域家族1，亚型A（RassfIA）和K-Ras，在介导Mst 1的激活，心肌细胞的生长和死亡中的作用，以及对心脏功能的影响。将对遗传改变的RassfIA和K-Ras小鼠进行横向主动脉缩窄，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、血液动力学分析、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心脏表型。RassfIA可以调节心脏纤维化的可能性也将通过关注NF-κ B作为潜在的介质来解决。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Mst 1的信号通路。这项工作还将寻求评估K-Ras作为心脏中这一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Mst 1在体内的调节机制，并应有助于更好地治疗心力衰竭的发展。

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.