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：
10653903
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/10653903
关键词：
Actins Acute 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 Cytoskeletal Proteins Cytoskeleton Data Development Development Plans Doctor of Philosophy Echocardiography Educational workshop Eligibility Determination 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 Institution Knowledge Laboratories Leadership Left Ligands LoxP-flanked allele Mediating Mentors Mentorship Metabolism Modeling Molecular Molecular Biology 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 right ventricular failure skills small hairpin RNA 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.

抽象的该申请中的提案概述了一项为期五年的职业发展计划，以准备候选人。医学博士乔纳森·爱德华兹（Jonathan Edwards）从事独立的身体科学家的职业生涯心室衰竭（RVF）。研究与发展计划经过精心构建，以扩大爱德华兹博士的通过在体外提供技术培训和专业知识，在心血管研究中的科学基础心肌细胞生物学，分子生物学，转基因鼠模型发展和RV的表征在鼠模型中的功能。爱德华兹博士的发展计划还将加强他的沟通，领导才能，通过参加高收益课程，讲习班和半小伙子参加的协作技能。 RVF是一个重大的健康问题，是死亡的有力预测指标，没有证明疗法。 RVF的分子机制缺乏人工或动物工作，这可能会促进在我们领域，迫切需要的新型RVF疗法的发展是一个很大的差距。我发现胎儿在严重的RVF患者的RV和患有小鼠的RV中，非规范的Wnt受体ROR2强烈重新激活来自压力超负荷的RVF。此外，该ROR2激活与ROR2/Ca2+的上调有关反应性蛋白质钙蛋白酶和靶蛋白裂解。我假设病理ROR2表达是一种新颖 RVF和病理心肌细胞重塑的潜在靶向分子驱动器，通过钙蛋白酶介导的细胞骨架和肌肉骨骼的破坏和凋亡依赖性Ca2+依赖性的凋亡方式。三个相互关联但独立的特定目的将解决这一假设：1）确定 ROR2体外心肌细胞细胞骨架和肉瘤破坏和凋亡的机械作用； 2）确定RV特异性ROR2过表达是否足以引起RVF； 3）确定RV ROR2是否表达对于压力超负荷引起的RVF是必需的。这项研究培训将根据医学博士Zoltan Arany博士的指导（牢房主任）进行。生物学，生理学和代谢），由Benjamin Prosser博士（副主任宾夕法尼亚大学的宾夕法尼亚大学肌肉研究所。爱德华兹博士汇集了一个跨学科咨询委员会具有体外心肌细胞生物学专业知识，分子生物学，转化科学， CA2+调节，WNT信号，RVF鼠建模，转基因动物模型开发和领导力。目前，他是一名符合董事会资格的儿科心脏病专家，儿科心肌病的高级临床研究员，心脏失败，心脏移植，以及在Arany实验室的博士后研究员。他的长期职业目标成为具有RV心肌生物学专业知识的身体科学家和儿科患者是儿科研究医院的学术教师。爱德华兹博士将从他的健壮和平衡的心态团队，研究环境和明确的分区中受益和机构承诺，所有这些都将支持他的独立之路。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Temporal trends in primary payers in pediatric heart transplant and association with long-term survival.

儿科心脏移植主要支付者的时间趋势及其与长期生存的关系。

DOI：
10.1111/petr.14484
发表时间：
2023
期刊：
Pediatric transplantation
影响因子：
1.3
作者：
Restaino,Kathryn;Zhang,Xuemei;Faerber,JenniferA;Rossano,JosephW;Burstein,Danielle;Wittlieb-Weber,CarolA;Lin,KimberlyYee;Edelson,JonathanB;Edwards,JonathanJ;O'Connor,MatthewJ
通讯作者：
O'Connor,MatthewJ