BMPR2 and the Pathogenesis of Pulmonary Hypertension

描述(由申请人提供)：原发性动脉高压(PAH)是一种以肺动脉血压升高、肺血管重塑和进行性右室肥厚为特征的疾病。尽管最近的治疗取得了进展，但近50%的PAH患者在确诊后5年内死亡。家族性PAH与编码II型骨形态发生蛋白受体(BMPR2)的基因杂合突变有关，但只有少数携带突变等位基因的个体会患上这种疾病。主要研究人员和他的团队开发了一系列带有BMPR2突变的转基因小鼠。他们发现，单独缺乏BMPR2并不能在小鼠体内持续复制多环芳烃。研究人员发现了BMPR2缺乏带来的意想不到的功能增强效应，包括观察到BMPR2杂合子肺血管细胞对转化生长因子和激活素A的反应更快。此外，研究人员还发现了第一个小分子BMP抑制剂，这将极大地促进BMP信号在体外和体内的研究。提出的研究分为三个目标。首先，BMPR2突变改变对转化生长因子和激活素A的反应以及它们的生理后遗症的机制将通过培养的肺血管细胞来阐明。其次，转基因小鼠将被用来检验BMPR2杂合子小鼠过度表达转化生长因子β和激活素A导致肺血管重构的假设。最后，研究人员计划使用他们的新型BMP抑制剂来确定BMP信号是否限制了PAH大鼠模型的肺血管重构。这项研究的结果不仅将为PAH的发病机制提供重要的见解，还可能为如何预防BMPR2突变患者的PAH发展提供线索。与公共卫生相关。肺动脉高压是一种影响肺血管的疾病，有时与编码II型骨形态发生受体(BMPR2)的基因突变有关。然而，只有少数携带BMPR2突变的患者会患上这种疾病。在这个项目中，携带BMPR2突变和一种新的BMP信号小分子抑制剂的小鼠将被用来研究BMPR2突变是如何导致疾病的，以及如何潜在地防止携带BMPR2突变的个体患上PAH。

DESCRIPTION (provided by applicant): Primary arterial hypertension (PAH) is a disease characterized by elevated pulmonary artery blood pressure, remodeling of the lung vasculature, and progressive right ventricular hypertrophy. Despite recent therapeutic advances, nearly 50% of PAH patients die within 5 years of diagnosis. The familial form of PAH is associated with heterozygous mutations in the gene encoding the type II bone morphogenetic protein receptor (BMPR2), but only a minority of individuals who carry a mutant allele develop the disease The principal investigator and his team have developed a series of genetically modified mice with BMPR2 mutations. They found that deficient BMPR2 alone does not consistently replicate PAH in mice. The investigators have found unanticipated gain-of-function effects of BMPR2 deficiency including the observation that BMPR2 heterozygous pulmonary vascular cells are more responsive to TGF¿ and activin A. Moreover, the investigators have identified the first small molecule BMP inhibitor which will greatly facilitate studies of BMP signaling both in vitro and in vivo. The proposed research is divided into three aims. First, the mechanisms by which BMPR2 mutations alter responses to TGF¿ and activin A, as well as their physiologic sequelae, will be elucidated using cultured pulmonary vascular cells. Second, genetically-modified mice will be used to test the hypothesis that overexpression of TGF¿ and activin A leads to pulmonary vascular remodeling in BMPR2 heterozygous mice. Finally, the investigators plan to use their novel BMP inhibitor to ascertain whether BMP signaling limits pulmonary vascular remodeling in a robust rat model of PAH. The results of the proposed studies will not only provide important insights into the pathogenesis of PAH but may also provide clues as to how to prevent the development of PAH in patients with BMPR2 mutations. PUBLIC HEALTH RELEVANCE. Pulmonary arterial hypertension is a disease afflicting blood vessels in the lung and is sometimes associated with mutations in the gene encoding the type II bone morphogenetic receptor (BMPR2). However, only a minority of patients with BMPR2 mutations develop the disease. In this project, mice carrying BMPR2 mutations and a novel small molecule inhibitor of BMP signaling will be used to investigate how BMPR2 mutations contribute to the disease and potentially how to prevent individuals with BMPR2 mutations from developing PAH.