Noncanonical Receptor Signaling in Pulmonary Arterial Hypertension

描述(由申请人提供)：这项建议是为未来的初级教员苏达山·拉贾戈帕尔博士提供一个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信号。拉贾戈帕尔博士目前正在接受团契培训 他在杜克大学医学中心学习心血管医学，并计划在莱夫科维茨博士的实验室进行有指导的研究，以进一步加强他的科学培训。三十多年来，莱夫科维茨博士一直是心血管信号领域的领导者，在培养成功的内科科学家方面有着长期的记录。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，该委员会将扩大培训经验，促进医生-科学家的职业发展。在初步研究中，我们已经确定了多功能适配器�-arrestin(�ARRS)蛋白的一个新功能。除了通过G蛋白偶联受体(GPCRs)调节信号外，我们还发现�ARRs还通过转化生长因子-�受体-II型骨形态发生蛋白受体(BMPR-II)调节信号。在人类中，BMPR-II功能缺失突变与肺动脉高压的发展有关，我们发现�ARR基因敲除小鼠对慢性缺氧的反应显著改变了肺动脉高压的发展。这项研究的目的是：1)确定转化生长因子受体在内皮素和前列环素受体的信号转导中的作用，这是治疗肺动脉高压的药物靶点；以及2)表征�和�受体信号轴在肺动脉高压中的相互作用。我们期望这些研究能为�受体如何调节这两类受体的信号传递，以及如何利用这种调节来治疗肺动脉高压带来重要的机械性见解。

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.