BMPR2 and the Pathogenesis of Pulmonary Hypertension

描述(由申请人提供)：原发性肺动脉高压(PPH)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40%的PPH患者在确诊后三年内死亡。家族性PPH是一种常染色体显性遗传，具有不完全外显性，并与编码II型骨形态发生蛋白受体(BMPR2)的基因突变有关。此外，约25%的散发性PPH患者也存在BMPR2突变。 首席研究员已经组建了一个多学科的科学家团队，目的是阐明BMPR2在PPH发病机制中的作用。研究人员已经开发出一系列带有BMPR2基因突变的转基因小鼠，以及带有条件BMPR2突变的小鼠。BMPR2小鼠在基线时被发现是正常的，但在长期低氧后比野生型小鼠表现出更大的肺动脉高压。 提出的研究分为四个目标。首先，我们将比较野生型和BMPR2小鼠的肺血管重塑对环境和药物刺激相关的动物模型中肺血管重构的反应。其次，将从转基因小鼠中分离肺血管内皮细胞和平滑肌细胞，并评估BMP调节细胞增殖、迁移和凋亡的能力。第三，将评估携带BMPR2突变并保持激酶活性的小鼠的肺血管结构和功能。最后，携带BMPR2条件性突变的小鼠将被用于研究血管内皮细胞和平滑肌细胞在肺动脉高压发病机制中的作用。 拟议的研究结果可能会为PPH的发病机制提供重要的见解，包括为什么只有一些BMPR2突变的患者会患上这种疾病。此外，这些研究可能会验证BMPR2小鼠作为筛选新药和旧药的有价值的模型，目的是识别可能导致PPH的因素。

DESCRIPTION (provided by applicant): Primary pulmonary hypertension (PPH) 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 40% of PPH patients die within three years of diagnosis. The familial form of PPH is inherited as an autosomal dominant trait with incomplete penetrance and has been associated with mutations in the gene encoding the type II bone morphogenetic protein receptor (BMPR2). Moreover, about 25% of patients with sporadic PPH also have BMPR2 mutations. The principal investigator has assembled a multidisciplinary team of scientists with the objective of elucidating the role of BMPR2 in the pathogenesis of PPH. The investigators have already developed a series of genetically modified mice with mutations in the BMPR2 gene, as well as mice with a conditional BMPR2 mutation. BMPR2 mice were found to be normal at baseline but develop greater pulmonary hypertension than wild type mice after prolonged hypoxia. The proposed research is divided into four aims. First, the pulmonary vascular remodeling response to environmental and pharmacologic stimuli associated with the development of pulmonary hypertension in animal models will be compared in wild type and BMPR2 mice. Second, pulmonary vascular endothelial and smooth muscle cells will be isolated from genetically modified mice, and the ability of BMP to modulate cell proliferation, migration, and apoptosis will be assessed. Third, pulmonary vascular structure and function will be evaluated in mice with BMPR2 mutations that retain kinase activity. Finally, mice with a conditional BMPR2 mutation will be used to investigate the contribution of endothelial and smooth muscle cells to the pathogenesis of pulmonary hypertension. The results of the proposed studies will likely provide important insights into the pathogenesis of PPH including why only some patients with BMPR2 mutations develop the disease. Moreover, these studies may validate BMPR2 mice as a valuable model with which to screen new and old drugs with the goal of identifying agents that may cause PPH in individuals predisposed to the disease.