Mechanistic studies of Mas receptor activation and its role in aortic aneurysm formation

Mas受体激活及其在主动脉瘤形成中作用的机制研究

基本信息

批准号：
9386011
负责人：
JAMES W WISLER
金额：
$ 16.14万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-15 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9386011
关键词：
ARNT gene Abdominal Aortic Aneurysm Academic Medical Centers Advisory Committees Agonist Aneurysm Angiotensin II Angiotensin II Type 1 Receptor Blockers Angiotensins Aortic Aneurysm Aortic Diseases Apolipoprotein E Arrestins Award Biochemical Biological Assay Biology Biophysical Process Biophysics Cardiovascular system Cell model Chest Coupling Cultured Cells Data Development Disease Disease model Effectiveness Endothelial Cells Etiology Faculty Fellowship Fibroblasts Fluorescence Fluorescence Spectroscopy Funding Future G-Protein-Coupled Receptors G-substrate GTP-Binding Proteins Goals Growth In Vitro Inborn Genetic Diseases Infusion procedures Instruction Investigation Knowledge Laboratories Lead Ligand Binding Ligands Marfan Syndrome Mediating Mediator of activation protein Medical Medicine Membrane Mentorship Mitogen-Activated Protein Kinases Modeling Molecular Molecular Conformation Monitor Mus Muscle Cells Operative Surgical Procedures Orphan Outcome Study Pathogenesis Pathogenicity Pathway interactions Pharmacology Phospholipids Physicians Physiological Play Positioning Attribute Prevention Prevention therapy Program Development Property Proteins Receptor Activation Receptor Signaling Receptor, Angiotensin, Type 1 Regulation Research Research Personnel Role Scaffolding Protein Scientist Secure Signal Pathway Signal Transduction Syndrome System Testing Therapeutic Therapeutic Agents Time Training Transducers Ultrasonography Vascular Smooth Muscle Work beta-arrestin bimanes biophysical analysis biophysical techniques career development experience in vivo in vivo Model inhibitor/antagonist innovation insight meetings member mouse model nanodisk novel novel therapeutics osmotic minipump programs protein activation public health relevance receptor receptor function reconstitution research and development subcutaneous targeted agent targeted treatment therapeutic development

项目摘要

PROJECT SUMMARY/ABSTRACT This proposal is a for a five-year research program for a future junior faculty member, Dr. James Wisler, for studying cardiovascular cellular signaling under the mentorship of Dr. Robert Lefkowitz. Dr. Wisler is currently in his fellowship training in Cardiovascular Medicine at Duke University Medical Center and plans to further his scientific training in the laboratory of Dr. Lefkowitz. Dr. Lefkowitz has been a leader in the fields of cellular signaling, and cardiovascular biology for nearly four decades and has a long track record of training successful physician-scientists. The research and career development program devised will include specialized instruction, attendance at local and national scientific meetings, and an advisory committee that will broaden the training experience and help best prepare Dr. Wisler to obtain independent investigator funding by the end of this award period. In preliminary studies, we have identified a novel mechanism of aortic aneurysm development in murine models of both sporadic thoracic and abdominal aortic aneurysms as well as in a murine model of Marfan Syndrome, an inherited disorder complicated by the development of aortic aneurysms. These results suggest this pathway may have a more global pathogenic role in aneurysmal disease. This signaling pathway is dependent on angiotensin type IA receptor signaling. In addition, this pathogenic signaling cascade is negatively regulated by another G protein-coupled receptor (GPCR), the MAS receptor. Although the MAS receptor was de-orphanized over a decade ago, controversy exists over the precise mechanisms of activation and signaling mediated via this receptor. The aims of this proposed research are to: 1) to define the transducer coupling and signaling profiles downstream of the MAS receptor; 2) to delineate the properties of Mas receptor activation using biophysical approaches; and 3) to determine if Mas receptor signaling effects aortic aneurysm formation. Our lab is in a unique position to answer these questions as we have unparalleled expertise in the investigation of in vitro and in vivo GPCR biology. We expect these studies to result in important insights into the molecular mechanisms of aortic aneurysm formation as well as how regulation of these mechanisms might be exploited therapeutically via targeting of a novel, counter-regulatory receptor.

项目摘要/摘要该建议是针对未来初级教师James Wisler博士的五年研究计划用于在Robert Lefkowitz博士的指导下研究心血管细胞信号传导。威斯勒博士是目前正在杜克大学医学中心接受他的心血管医学研究金培训，并计划进一步在Lefkowitz博士的实验室进行了科学培训。 Lefkowitz博士一直是蜂窝信号传导和心血管生物学已有近四十年的历史成功的医师科学家。设计和职业发展计划设计的将包括专业教学，当地和国家科学会议的出席以及一个咨询委员会扩大培训经验并帮助最好的维斯勒博士通过这个奖励期结束。在初步研究中，我们已经确定了一种新型主动脉瘤的机制散发性胸腔和腹主动脉瘤以及鼠模型的开发以及 Marfan综合征的鼠模型，一种遗传性疾病，因主动脉动脉瘤的发展而复杂。这些结果表明该途径在动脉瘤疾病中可能具有更全球性的致病作用。这信号通路取决于血管紧张素IA受体信号传导。另外，这种致病信号传导级联反应受另一G蛋白偶联受体（GPCR），MAS受体负面调节。虽然十年前，MAS受体被脱非形化，争议在确切机制上存在通过该受体介导的激活和信号传导。这项拟议研究的目的是：1）定义 MAS受体下游的换能器耦合和信号传导曲线； 2）描绘 MAS受体使用生物物理方法激活； 3）确定MAS受体信号是否效应主动脉动脉瘤形成。我们的实验室处于独特的位置，可以回答这些问题，因为我们无与伦比研究体外和体内GPCR生物学研究方面的专业知识。我们预计这些研究会导致对主动脉瘤形成的分子机制的重要见解以及如何调节这些机制可以通过靶向新型的反调节受体来治疗。