Stretch-dependent X-ROS signaling: implications for cardiomyopathy

“拉伸依赖性X-ROS信号传导：对心肌病的影响” PI：Benjamin L.普罗瑟 心脏细胞中的一种新的信号通路，称为X-ROS信号通路，将心脏细胞的延长与 苯并咪唑对活性氧（ROS）和亚细胞Ca 2+信号传导的产生的影响（Prosser等人， Science 2011）。由PI发现并表征，X-ROS信号转导调节Ca 2+从 肌浆网储存在心脏细胞中。虽然X-ROS信号传导是一种正常的生理机制， 在疾病过程中上调（例如杜氏肌营养不良症），并可触发Ca 2+依赖性 心律不齐使用创新技术，将细胞长度控制与膜片钳技术联合收割机相结合， 电生理学，PI将表征该生理代的未知关键生物物理特征 的ROS，并研究信号级联的结果。单心脏的这种生物物理特征 细胞将在世界领先的W. J. Lederer博士（导师，马里兰州大学）的指导下进行， 心脏细胞电生理学和钙成像。 通过采用新技术和培训，PI下一步将从细胞中转移X-ROS信号， 水平到整个心脏的水平。PI将在完整的Langendorff灌注的 心脏舒张期长度由前负荷压力的变化调节。这些冗长的考试- 正如我们最近的证据所表明的那样，在健康和患病的心脏中都将进行依赖性信号传导 过度活跃的X-ROS可能与疾病中的钙依赖性心律失常有关。这些研究报告将 由大卫卡斯博士（共同导师，约翰霍普金斯医学院）指导，他是一位翻译心脏病专家， 专门研究ROS信号在心肌病中的作用。作为一名临床科学家，卡斯博士将扩大 PI的观点和技能，这将使PI采取更综合的方法来开展工作。 PI已经组建了一个优秀的研究咨询委员会，该委员会将提供培训和支持， 促进拟定的研究和PI的发展。PI将继续留在马里兰州，但将工作 在整个工作期间，在Lederer博士和Kass博士的指导下。此外，PI 获得国家的最先进的设备，以及优秀的资源，在大学的职业发展 马里兰州和约翰霍普金斯。拟定的工作和发展计划将使PI能够描述 X-ROS信号从亚细胞到整个心脏的生理和病理生理作用 水平，从而使他能够雕刻他的利基作为一个独立的教员。拟议方案是 PI长期目标的一部分是研究心脏功能的分子机制，特别关注 ROS和Ca 2+信号，并将这些知识应用于临床相关的条件。

"Stretch-dependent X-ROS signaling: implications for cardiomyopathy" PI: Benjamin L. Prosser A novel signaling pathway in heart cells, termed X-ROS signaling, links the lengthening of a heart cell during diastole to the generation of reactive oxygen species (ROS) and subcellular Ca2+ signaling (Prosser et al., Science 2011). Discovered and characterized by the PI, X-ROS signaling regulates the release of Ca2+ from sarcoplasmic reticulum stores in heart cells. While X-ROS signaling is a normal physiological mechanism, it is upregulated in disease processes (e.g. Duchenne muscular dystrophy) and can trigger Ca2+-dependent arrhythmias. Using innovative techniques that combine the control of cell length with patch-clamp electrophysiology, the PI will characterize unknown critical biophysical features of this physiological generation of ROS, and investigate the signaling cascade that results. This biophysical characterization in single heart cells will be performed under the guidance of Dr. W.J. Lederer (mentor, University of Maryland), a world leader in cardiac cellular electrophysiology and calcium imaging. Through the adoption of new techniques and training, the PI will next move X-ROS signaling from the cellular level to that of the whole heart. The PI will image ROS and calcium signaling in intact, Langendorff-perfused hearts where diastolic length is modulated by a change in pre-load pressure. These examinations of length- dependent signaling will be conducted in both healthy and diseased hearts, as our recent evidence suggests that hyper-active X-ROS may be linked to calcium-dependent arrhythmia in disease. These studies will be guided by Dr. David Kass (co-mentor, Johns Hopkins School of Medicine), a translational cardiologist who specializes in the role of ROS signaling in cardiomyopathy. As a clinician scientist, Dr. Kass will broaden the perspective and skill set of the PI, which will allow the PI to take a more integrative approach to his work. The PI has assembled an excellent research advisory committee who will provide the training and support to facilitate the proposed studies and the growth of the PI. The PI will remain based at Maryland, but will work under the guidance of both Drs. Lederer and Kass during the entire period of work. Additionally, the PI has access to state-of-the-art equipment, as well as excellent resources for career development at the University of Maryland and at Johns Hopkins. The proposed work and development plan will enable the PI to characterize the physiological and pathophysiological actions of X-ROS signaling from the subcellular to the whole heart level, and will thus enable him to carve his niche as an independent faculty member. The proposed program is part of the PI's long term goal to investigate molecular mechanisms of cardiac function, with a particular focus on ROS and Ca2+ signaling, and to apply this knowledge to clinically relevant conditions.