Defining the Role of ROR2 in Right Ventricular Failure Pathogenesis

摘要 这份申请书中的建议概述了一个五年的职业发展计划，为候选人做好准备。 乔纳森·爱德华兹，医学博士，作为一名定义权利机制的独立内科医生兼科学家 心衰(RVF)。研发计划经过精心设计，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提供科学基础 心肌细胞生物学、分子生物学、转基因小鼠模型的建立和轮状病毒的特性 在小鼠模型中发挥作用。爱德华兹博士的发展计划还将加强他的沟通、领导力、 通过参加高收益的课程、研讨会和研讨会来培养合作技能。 裂谷热是一种重要的健康问题，是死亡的强烈预测因素，目前还没有得到证实。 治疗。缺乏人类或动物对RVF分子机制的研究，这可能会促进 开发急需的新型RVF疗法，是我们领域的一个重大空白。我发现那个胎儿 非典型WNT受体ROR2在严重RVF患者和WVF小鼠的RV中强烈重新激活 压力过载引起的RVF。此外，这种ROR2的激活与ROR2/Ca2的上调有关 反应性蛋白水解酶、钙蛋白酶和靶蛋白的裂解。我假设病理性ROR2的表达是一种新的 以及RVF和病理性心肌细胞重塑的潜在靶向分子驱动因素，后者通过 钙激活蛋白介导的细胞骨架和亚细胞内钙依赖性肌瘤的破坏和凋亡 举止。三个相互关联但独立的具体目标将解决这一假设：1)确定 Ror2在体外培养心肌细胞骨架及肌瘤断裂和凋亡中的作用 确定RV特异性Ror2过度表达是否足以引起RVF；以及3)确定RV Ror2表达是否 对于压力过载引起的右室颤动是必要的。 本次研究培训将在Zoltan Arany博士、医学博士、博士(细胞主任)的指导下进行 生物学、生理学和新陈代谢)，由Benjamin Prosser博士(副主任， 宾夕法尼亚大学肌肉学院)。爱德华兹博士已经组建了一个跨学科的 在体外心肌细胞生物学、分子生物学、翻译科学方面具有专长的咨询委员会， CA2调控，WNT信号，RVF小鼠模型，转基因动物模型开发，以及领导力。 目前，他是具有董事会资格的儿科心脏病专家，儿科心肌病、心脏病的高级临床研究员。 失败，心脏移植，以及阿兰尼实验室的博士后研究员。他的长期职业目标 是一名内科科学家，在右室心肌生物学和临床管理方面具有专业知识 在儿科研究医院担任学术教员的心力衰竭儿科患者。爱德华兹博士 将受益于他强大而平衡的指导团队、研究环境和明确的部门 和机构承诺，所有这些都将支持他走向独立的道路。

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.