Stretch-dependent X-ROS signaling: implications for cardiomyopathy

PI: Benjamin L. Prosser心脏细胞中的一种新的信号通路，称为X-ROS信号，将舒张期心脏细胞的延长与活性氧（ROS）和亚细胞Ca2+信号的产生联系起来（Prosser et al., Science 2011）。由PI发现并表征的X-ROS信号调节心肌细胞中肌浆网储存Ca2+的释放。虽然X-ROS信号是一种正常的生理机制，但它在疾病过程中（例如杜氏肌营养不良）上调，并可引发Ca2+依赖性心律失常。利用结合细胞长度控制和膜片钳电生理学的创新技术，PI将描述这种生理生成ROS的未知关键生物物理特征，并研究由此产生的信号级联。这项单个心脏细胞的生物物理表征将在W.J. Lederer博士（马里兰大学导师）的指导下进行，他是心脏细胞电生理学和钙成像领域的世界领导者。通过采用新技术和训练，PI下一步将把X-ROS信号从细胞水平转移到整个心脏水平。PI将成像完整的，langendorff灌注心脏的ROS和钙信号，其中舒张期长度是由负荷前压力变化调节的。这些长度依赖性信号的检查将在健康和患病的心脏中进行，因为我们最近的证据表明，过度活跃的X-ROS可能与疾病中钙依赖性心律失常有关。这些研究将由David Kass博士（约翰霍普金斯医学院的共同导师）指导，他是一位专攻ROS信号在心肌病中的作用的转译心脏病专家。作为一名临床科学家，卡斯博士将拓宽PI的视角和技能，这将使PI能够采取更综合的方法来开展工作。警务处成立了一个优秀的研究咨询委员会，为拟议的研究和警务处的发展提供培训和支持。PI将继续以马里兰为基地，但将在两位博士的指导下工作。Lederer和Kass在整个工作期间。此外，PI可以使用最先进的设备，以及马里兰大学和约翰霍普金斯大学职业发展的优秀资源。所提出的工作和发展计划将使PI能够表征从亚细胞到整个心脏水平的X-ROS信号的生理和病理生理作用，从而使他能够成为一名独立的教员。该计划是PI长期目标的一部分，旨在研究心脏功能的分子机制，特别关注ROS和Ca2+信号，并将这些知识应用于临床相关疾病。

DESCRIPTION (provided by applicant): "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 allo 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.