Defining the Role of ROR2 in Right Ventricular Failure Pathogenesis

定义 ROR2 在右心室衰竭发病机制中的作用

基本信息

批准号：
10283469
负责人：
Jonathan Joseph Edwards
金额：
$ 13.14万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-10 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10283469
关键词：
Actins Acute Address Advisory Committees American Animals Apoptosis Biology Calpain Cardiac Myocytes Cardiovascular system Cell Surface Receptors Cellular biology Cessation of life Clinical Clinical Management Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Communication Complementary DNA Complex Critical Thinking Cytoskeleton Data Development Development Plans Doctor of Philosophy Echocardiography Educational workshop Environment Epidemiology F-Actin FLNA gene Faculty Failure Flow Cytometry Fostering Foundations Funding Gene Expression Profile Genes Goals Guide RNA Health Heart Heart Transplantation Heart failure Histology Hospitals Human Human Rights In Vitro Institutes Knowledge Laboratories Leadership Left Ligands LoxP-flanked allele Mediating Mentors Mentorship Metabolism Modeling Molecular Molecular Biology Molecular Target Mus Muscle Muscle Cells Myocardial Neonatal Neurons Oryctolagus cuniculus Pathogenesis Pathologic Pathology Pathway interactions Patients Pediatric Cardiomyopathy Pediatric Research Pennsylvania Peptide Hydrolases Phenotype Physicians Physiology Postdoctoral Fellow Proteolysis Pulmonary artery structure Rattus Recombinants Regulation Research Research Personnel Research Training Role Sampling Scientist Structure Technical Expertise Testing Training Training Programs Transgenic Animals Transgenic Organisms Translational Research Treatment Failure Universities Up-Regulation Ventricular WNT Signaling Pathway WNT5A gene Western Blotting Work alpha Actinin animal model development cancer cell career career development differential expression extracellular fetal gain of function hemodynamics in vivo in vivo Model insight knock-down loss of function member model development mortality mortality risk mouse model novel overexpression pediatric cardiologist pediatric patients pressure public health relevance receptor research and development skills small hairpin RNA targeted treatment therapeutic target treatment response

项目摘要

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.

抽象的本申请中的提案概述了一个五年职业发展计划，旨在为候选人博士做好准备。乔纳森·爱德华兹（Jonathan Edwards）医学博士，作为一名独立的医师科学家定义权利机制心室衰竭（RVF）的研究和开发计划经过精心设计，以扩大爱德华兹博士的研究范围。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 表征爱德华兹博士的发展计划也将加强他的沟通、领导力、通过参加高成果课程、讲习班和研讨会来提高协作技能。裂谷热是一种严重的健康问题，是死亡的有力预测因素，但目前尚无证据证明这一问题缺乏对 RVF 分子机制的人类或动物研究，这可能会促进治疗。我发现，开发急需的新型裂谷热疗法是我们领域的一个重大差距。非经典 WNT 受体 ROR2 在严重 RVF 患者和患有 RVF 的小鼠的 RV 中强烈重新激活此外，这种 ROR2 激活与 ROR2/Ca2+ 的上调有关。响应性蛋白酶钙蛋白酶和靶蛋白裂解我认为病理性 ROR2 表达是一种新颖的。 RVF 和病理性心肌细胞重塑的潜在可靶向分子驱动因素，其作用通过钙蛋白酶介导的亚细胞 Ca2+ 依赖性细胞骨架和肌节破坏和凋亡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 体外心肌细胞骨架和肌节破坏和细胞凋亡的机制作用 2) 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 表达是否足够对于压力过载引起的 RVF 是必要的。这项研究培训将在 Zoltan Arany 博士（医学博士、哲学博士）（Cell 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，宾夕法尼亚大学的宾夕法尼亚肌肉研究所 (Penn Muscle Institute) 爱德华兹博士组建了一个跨学科的机构。咨询委员会在体外心肌细胞生物学、分子生物学、转化科学、 Ca2+ 调节、WNT 信号传导、RVF 小鼠模型、转基因动物模型开发和领导力。目前，他是一名符合委员会资格的儿科心脏病专家、儿科心肌病、心脏疾病的高级临床研究员。失败和心脏移植，以及阿兰尼实验室的博士后研究员他的长期职业目标。是一名拥有 RV 心肌生物学和临床管理专业知识的医师科学家爱德华兹博士是一家儿科研究医院的学术教员，负责治疗患有心力衰竭的儿科患者。将受益于他强大而平衡的导师团队、研究环境和明确的部门和制度承诺，所有这些都将支持他的独立之路。