Noncanonical Receptor Signaling in Pulmonary Arterial Hypertension

描述（由申请人提供）：本提案是为未来的初级教员Sudarshan Rajagopal博士提供的一个为期五年的研究项目，该项目在Robert Lefkowitz博士的指导下研究心血管信号。Rajagopal博士目前正在接受奖学金培训 他在杜克大学医学中心从事心血管医学研究，并计划在莱夫科维茨博士的实验室进行指导研究，以进一步加强他的科学训练。Lefkowitz博士在心血管信号领域已经领导了三十多年，并且在培养成功的医生科学家方面有着悠久的历史。该研究计划将包括专门的指导，参加科学会议，以及一个咨询委员会，将扩大培训经验，促进职业发展作为一个医生，科学家。在初步研究中，我们已经确定了一个新的多功能适配器<$arrestin（<$arrs）蛋白的作用。除了它们在G蛋白偶联受体（GPCR）信号传导中的典型作用外，我们还发现Δ arrs还调节II型骨形态发生蛋白受体（BMPR-II）（一种TGF-Δ受体）的信号传导。在人类中，BMPR-II的功能缺失突变与肺动脉高压（PAH）的发展有关，我们发现，BMPR-II基因敲除小鼠在慢性缺氧时明显改变了PAH的发展。这项拟议研究的目的是：1）确定<$arrs在内皮素和前列环素受体（PAH治疗中的药物靶点）信号传导中的作用; 2）表征PAH中GPCR和TGF-<$受体信号传导轴之间的串扰。我们希望这些研究能够产生重要的机制见解，了解arrs如何调节这两类受体的信号传导，以及如何利用这种调节来获得PAH的治疗益处。

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.