Defining the Role of ROR2 in Right Ventricular Failure Pathogenesis

摘要 本申请中的建议书概述了一个五年职业发展计划，以准备候选人，博士。 乔纳森爱德华兹，医学博士，作为一个独立的医生，科学家的职业生涯定义的权利机制 心室衰竭（RVF）。研究和开发计划是精心设计的，以扩大爱德华兹博士的 通过提供体外技术培训和专业知识，为心血管研究奠定科学基础 心肌细胞生物学、分子生物学、转基因小鼠模型开发和RV的表征 在小鼠模型中的功能。爱德华兹博士的发展计划也将加强他的沟通，领导， 通过参加高产出的课程、讲习班和研讨会来提高学生的学习能力和协作技能。 裂谷热是一个严重的健康问题，是死亡的有力预测因素， 治疗缺乏对裂谷热分子机制的人类或动物研究， 开发亟需的裂谷热新疗法，是我们领域的一个重大空白。我发现胎儿 非经典WNT受体ROR 2在严重RVF患者的RV和患有RVF的小鼠中被强烈再激活。 压力过载导致裂谷热。此外，这种ROR 2激活与ROR 2/Ca 2+的上调有关。 应答性蛋白酶钙蛋白酶和靶蛋白切割。我假设病理性ROR 2表达是一种新的 和RVF和病理性心肌细胞重塑的潜在靶向分子驱动因子，其通过 钙蛋白酶介导的细胞骨架和肌节破坏和细胞凋亡在亚细胞钙依赖性 方式三个相互关联但独立的具体目标将解决这一假设：1）确定 Ror 2在体外心肌细胞骨架和肌节破坏和凋亡中的机制作用; 2） 确定RV特异性Ror 2过表达是否足以引起RVF;以及3）确定RV Ror 2表达是否 是压力过载引起裂谷热所必需的。 本研究培训将在Zoltan Arany博士（MD，PhD）（细胞研究中心主任）的指导下进行 生物学，生理学和代谢），与共同导师博士本杰明Prosser，博士（副主任， 宾夕法尼亚大学肌肉研究所）。爱德华兹博士组织了一个跨学科的 咨询委员会，具有体外心肌细胞生物学、分子生物学、转化科学 钙离子调节，WNT信号，裂谷热小鼠模型，转基因动物模型的开发，和领导。 目前，他是一名符合董事会资格的儿科心脏病专家，儿科心肌病高级临床研究员， 失败和心脏移植，以及Arany实验室的博士后研究员。他的长期职业目标 是作为一名具有RV心肌生物学和临床管理专业知识的医生-科学家， 在一家儿科研究医院担任学术教员的心力衰竭儿科患者。爱德华兹医生 将受益于他强大而平衡的导师团队，研究环境，以及明确的部门 和体制承诺，所有这些都将支持他走向独立。

ABSTRACT The proposal in this application outlines a five-year career development plan to prepare the candidate, Dr. Jonathan Edwards, MD, for a career as an independent physician-scientist defining mechanisms of right ventricular failure (RVF). The research and development plans are carefully structured to expand Dr. Edwards’s scientific foundation in cardiovascular research by providing technical training and expertise in in vitro cardiomyocyte biology, molecular biology, transgenic murine model development, and characterization of RV function in murine models. Dr. Edwards’s development plan will also strengthen his communication, leadership, and collaboration skills through attendance of high yield coursework, workshops, and seminars. RVF is a significant health problem that is a strong predictor of death, and for which there are no proven therapies. The lack of human or animal work investigating molecular mechanisms of RVF, which could foster the development of critically needed novel RVF therapies, is a significant gap in our field. I found that the fetal noncanonical WNT receptor ROR2 is strongly reactivated in the RV of patients with severe RVF and in mice with RVF from pressure overload. Further, this ROR2 activation was associated with upregulation of the ROR2/Ca2+ responsive protease calpain and target protein cleavage. I hypothesize that pathologic ROR2 expression is a novel and potentially targetable molecular driver of RVF and pathologic cardiomyocyte remodeling, which acts via calpain-mediated cytoskeleton and sarcomeric disruption and apoptosis in a subcellular Ca2+-dependent manner. Three interrelated, but independent Specific Aims will address this hypothesis: 1) Determine the mechanistic role for Ror2 in in vitro cardiomyocyte cytoskeleton and sarcomeric disruption and apoptosis; 2) Determine if RV-specific Ror2 overexpression is sufficient to cause RVF; and 3) Determine if RV Ror2 expression is necessary for pressure overload-induced RVF. This research training will be conducted under the mentorship of Dr. Zoltan Arany, MD, PhD (Director, Cell Biology, Physiology, and Metabolism), with co-mentorship by Dr. Benjamin Prosser, PhD (Associate Director, Penn Muscle Institute) at the University of Pennsylvania. Dr. Edwards has assembled an interdisciplinary advisory committee with expertise in in vitro cardiomyocyte biology, molecular biology, translational science, Ca2+ regulation, WNT signaling, RVF murine modeling, transgenic animal model development, and leadership. Currently he is a board-eligible pediatric cardiologist, advanced clinical fellow in pediatric cardiomyopathy, heart failure, and heart transplantation, and a postdoctoral fellow in the Arany laboratory. His long-term career goals are to serve as a physician-scientist with expertise in RV myocardial biology and the clinical management of pediatric patients with heart failure as an academic faculty member at a pediatric research hospital. Dr. Edwards will benefit from his robust and balanced mentorship team, research environment, and unequivocal divisional and institutional commitment, all of which will support his path to independence.