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

项目摘要/摘要 这项提议是一项针对未来初级教员詹姆斯·威斯勒博士的为期五年的研究计划， 在罗伯特·莱夫科维茨博士的指导下研究心血管细胞信号。威斯勒博士是 目前在杜克大学医学中心接受心血管医学研究员培训，并计划 在莱夫科维茨博士的实验室继续他的科学训练。莱夫科维茨博士一直是以下领域的领导者 在细胞信号和心血管生物学方面有近40年的经验，并有长期的培训记录 成功的内科医生-科学家。制定的研究和职业发展计划将包括 专门指导，参加地方和国家科学会议，以及一个咨询委员会，将 通过以下方式扩大培训经验并帮助威斯勒博士做好获得独立研究人员资金的最佳准备 获奖期结束。在初步研究中，我们发现了一种新的主动脉瘤发病机制。 小鼠散发性胸主动脉瘤和腹主动脉瘤模型的研究进展 马凡综合征的小鼠模型，这是一种遗传性疾病，合并主动脉瘤的发展。 这些结果表明，这一途径在动脉瘤性疾病中可能具有更全球性的致病作用。这 信号通路依赖于血管紧张素A受体信号通路。此外，这种致病信号 CASCADE受另一种G蛋白偶联受体(GPCR)--MAS受体的负调控。虽然 MAS受体在十多年前就被去孤儿了，但对其确切的机制仍存在争议 通过该受体介导的激活和信号传递。这项拟议研究的目的是：1)定义 MAS受体下游的转导偶联和信号分布；2)描绘 使用生物物理方法激活Mas受体；以及3)确定Mas受体信号转导 主动脉瘤形成。我们的实验室在回答这些问题方面处于独一无二的地位，因为我们的 在体外和体内GPCR生物学研究方面的专业知识。我们预计这些研究将导致 对主动脉瘤形成的分子机制以及如何调控的重要见解 这些机制可以通过靶向一种新的、反调节受体来用于治疗。

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.