Noncanonical Receptor Signaling in Pulmonary Arterial Hypertension

肺动脉高压中的非典型受体信号传导

基本信息

批准号：
8714035
负责人：
Sudarshan K Rajagopal
金额：
$ 10.26万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8714035
关键词：
ARRB1 gene Academic Medical Centers Advisory Committees Agonist Arr2 Arrestins Binding Biological Assay Biology Blood Vessels Cardiovascular system Cell Culture System Cell Nucleus Chemicals Chronic Development Disease Drug Targeting Endothelial Cells Endothelin Endothelin Receptor Epoprostenol Receptors Faculty Failure Fellowship Fostering Functional disorder Future G Protein-Coupled Receptor Signaling G-Protein Signaling Pathway G-Protein-Coupled Receptors GTP-Binding Proteins Heart Heterotrimeric GTP-Binding Proteins Human Hypoxia Incidence Infusion procedures Instruction Knockout Mice Laboratories Lead Ligands Lung Mass Spectrum Analysis Mediating Mediator of activation protein Medical Medicine Mentors Mentorship Mutation Pathogenesis Pathway interactions Patients Pattern Phenotype Phosphorylation Physicians Physiological Play Prostaglandins I Proteins Pulmonary Hypertension Pulmonary Vascular Resistance Pulmonary artery structure Rare Diseases Receptor Signaling Registries Regulation Relative (related person)Research Right Ventricular Dysfunction Right Ventricular Hypertrophy Right-On Rodent Model Role Scientist Second Messenger Systems Side Signal Transduction Small Interfering RNA Smooth Muscle Myocytes Stress Testing Therapeutic Therapeutic Agents Time Training Transducers United States United States National Institutes of Health Ventricular Western Blotting Wild Type Mouse adapter protein arrestin 1 base bone morphogenetic protein receptor type II career development cost desensitization experience inhibitor/antagonist insight loss of function mutation meetings member novel novel therapeutics outcome forecast programs public health relevance pulmonary arterial hypertension receptor response scaffold second messenger transcription factor

项目摘要

DESCRIPTION (provided by applicant): This proposal is for a five-year research program for a future junior faculty member, Dr. Sudarshan Rajagopal, in studying cardiovascular signaling under the mentorship of Dr. Robert Lefkowitz. Dr. Rajagopal is currently in his fellowship training in cardiovascular medicine at Duke University Medical Center and plans to further his scientific training with mentored research in Dr. Lefkowitz's laboratory. Dr. Lefkowitz has been a leader in the field of cardiovascular signaling for over three decades and has a long track record of training successful physician-scientists. The research program will include specialized instruction, attendance at scientific meetings, and an advisory committee that will broaden the training experience and foster career development as a physician-scientist. In preliminary studies, we have identified a novel role for the multifunctional adapter ¿- arrestin (¿arrs) proteins. In addition to their canonical role in signaling by G protein-coupled receptors (GPCRs), we have found that ¿arrs also regulate signaling by the type II bone morphogenetic protein receptor (BMPR-II), a TGF-¿ receptor. In humans, loss-of-function mutations of BMPR-II are associated with the development of pulmonary arterial hypertension (PAH), and we have found that ¿arr knockout mice have markedly altered development of PAH in response to chronic hypoxia. The aims of this proposed research are to: 1) Determine the role of ¿arrs in signaling by endothelin and prostacyclin receptors, drug targets in the treatment of PAH; and 2) Characterize cross-talk between the GPCR and TGF-¿ receptor signaling axes in PAH. We expect these studies to yield important mechanistic insights into how ¿arrs regulate signaling by these two classes of receptors and how such regulation could be exploited for therapeutic benefit in PAH.

描述（由应用程序提供）：该建议是针对未来初级教师Sudarshan Rajagopal博士的五年研究计划，在研究Robert Lefkowitz博士的心态下研究心血管信号。 Rajagopal博士目前正在接受奖学金培训杜克大学医学中心（Duke University Center）的心血管医学博士学位，并计划通过在Lefkowitz博士的实验室进行指导的研究进一步进一步培训。 Lefkowitz博士一直是心血管信号领域的领导者，已有三十多年的历史，并且在训练成功的身体科学家方面有着悠久的记录。该研究计划将包括专业指导，参加科学会议的出席以及将扩大培训经验并促进职业发展的咨询委员会。在初步研究中，我们确定了多功能衔接子�-抑制蛋白（ARRS）蛋白的新作用。除了通过G蛋白偶联受体（GPCR）在信号传导中的规范作用外，我们还发现，ARR还通过II型骨形态发生蛋白受体（BMPR-II）调节信号，TGF-接收器。在人类中，BMPR-II的功能丧失突变与肺动脉高压（PAH）的发展有关，我们发现``ARR敲除小鼠因慢性缺氧而显着改变了PAH的发育。这项拟议的研究的目的是：1）确定内皮素和前列环素受体在信号传导中的作用，药物靶标在PAH治疗中的作用； 2）表征PAH中GPCR和TGF-oo接收器信号轴之间的串扰。我们希望这些研究能够对„ ARR如何通过这两类接收器调节信号的信号以及如何探索该调节以在PAH中进行治疗益处来调节信号传导。