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

• 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
• 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

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.

项目总结/摘要 这个建议是一个为期五年的研究计划，为未来的初级教员，博士詹姆斯Wisler， 在罗伯特·莱夫科维茨博士的指导下研究心血管细胞信号。Wisler博士是 目前在杜克大学医学中心接受心血管医学的奖学金培训，并计划 在莱夫科维茨博士的实验室进一步接受科学培训。莱夫科维茨博士一直是 细胞信号和心血管生物学近四十年，并有长期的培训记录 成功的物理学家所设计的研究和职业发展计划将包括 专业指导，参加地方和国家科学会议，以及一个咨询委员会， 通过以下方式拓宽培训经验，帮助Wisler博士为获得独立研究者资助做好最好的准备 这个奖励期的结束。在初步研究中，我们已经确定了一种新的机制，主动脉瘤 在散发性胸主动脉瘤和腹主动脉瘤的小鼠模型中， 马凡氏综合征的小鼠模型，马凡氏综合征是一种由主动脉瘤发展而复杂化的遗传性疾病。 这些结果表明，这一途径可能有一个更全球性的致病作用，脑血管疾病。这 信号传导途径依赖于血管紧张素IA型受体信号传导。此外，这种致病信号 级联反应受另一种G蛋白偶联受体（GPCR）MAS受体负调控。虽然 MAS受体在十多年前就被去活化了，但对MAS受体的确切机制仍存在争议。 通过该受体介导的激活和信号传导。这项研究的目的是：1）定义 MAS受体下游的换能器偶联和信号传导谱; 2）描绘 使用生物物理方法的Mas受体活化;和3）确定Mas受体信号传导是否影响 主动脉瘤形成。我们的实验室处于一个独特的位置来回答这些问题，因为我们有无与伦比的 在体外和体内GPCR生物学研究方面的专业知识。我们希望这些研究能带来 对主动脉瘤形成的分子机制以及如何调节 这些机制可以通过靶向新的反调节受体而在治疗上加以利用。