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心室肥大为特征的疾病。 尽管最近的治疗进展，近40%的PPH患者在诊断后三年内死亡。 家族性PPH是一种常染色体显性遗传，具有不完全遗传性，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患者也有BMPR2突变。 主要研究者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。 研究人员已经开发了一系列BMPR2基因突变的转基因小鼠，以及具有条件性BMPR2突变的小鼠。 发现BMPR2小鼠在基线时是正常的，但在长时间缺氧后比野生型小鼠发展更大的肺动脉高压。 拟议的研究分为四个目标。 首先，将在野生型和BMPR2小鼠中比较动物模型中与肺动脉高压发展相关的对环境和药理学刺激的肺血管重构反应。 第二，肺血管内皮细胞和平滑肌细胞将从遗传修饰的小鼠中分离，并将评估BMP调节细胞增殖、迁移和凋亡的能力。 第三，将在具有保留激酶活性的BMPR2突变的小鼠中评价肺血管结构和功能。 最后，具有条件性BMPR2突变的小鼠将用于研究内皮细胞和平滑肌细胞对肺动脉高压发病机制的贡献。 拟议研究的结果可能会为PPH的发病机制提供重要见解，包括为什么只有一些具有BMPR2突变的患者才会患上这种疾病。 此外，这些研究可能会验证BMPR2小鼠作为一个有价值的模型，以筛选新的和旧的药物，目的是确定代理，可能会导致PPH的个人倾向于这种疾病。

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.