Interrogation of the Cellular Pathogenesis of Pulmonary Hypertension

肺动脉高压（PH）是一种进行性疾病，定义为平均肺动脉压升高超过25 mm Hg，导致右心衰竭和显著的死亡风险。TGF β超家族途径的两个成员骨形态发生蛋白受体II（BMPR II）和TGF-β受体I（ALK 1）的遗传改变与PH的发病机制有关。尽管TGF β途径具有遗传和功能意义，但目前尚不清楚TGF信号转导的失调如何导致PAH。我们推测PAH的发生是由于内皮细胞内TGF信号的不平衡。具体地，内皮细胞中增强的TGF信号传导促进表型变化，其允许细胞经历内皮-间充质转化并有助于平滑肌或肌成纤维细胞群体。该项目解决了肺动脉高压的基本问题之一，即TGF β信号传导改变导致PH发病机制的机制。TGF β参与的无数细胞过程和多种细胞类型放大了这个问题的复杂性。（内皮、平滑肌和外膜成纤维细胞），其能够影响并且可能影响肺动脉高压的发展。为了开始解决分子途径，本项目提出研究TGF β信号转导在内皮细胞中的作用。我们将依靠内皮细胞诱导的TGF β受体II缺失和PH的成熟缺氧模型来证明内皮细胞TGF β信号传导在PH发展中的作用。内皮-间充质转化的特征在于遗传标记内皮细胞并在暴露于慢性缺氧后跟踪其命运。最后，我们将证明TGF β信号转导是内皮-间充质转化所必需的，并测试一种新的TGF β介导的转化抑制剂。了解这种情况发生的分子机制可以深入了解人类PAH的启动和新的治疗靶点的开发。

Pulmonary arterial hypertension (PH), a progressive disease defined by an elevation in the mean pulmonary artery pressure above 25 mm Hg, leads to right heart failure and a significant risk of death. Genetic alterations in two members of the TGF beta superfamily pathways, bone morphogenetic protein receptor II (BMPR II) and the TGF-beta receptor I, ALK1, have been implicated in the pathogenesis of PH. Despite the genetic and functional significance of the TGF pathway, it is unclear how dysregulation of TGF signaling results in PAH. We hypothesize that the development of PAH results from an imbalance in TGF signaling within endothelial cells. Specifically, enhanced TGF signaling in endothelial cells promotes a phenotypic change that allows the cells to undergo endothelial-mesenchymal transition and contribute to the smooth muscle or myofibroblast cell population. This project addresses one of the fundamental questions in pulmonary hypertension, the mechanism by which altered TGF beta signaling contributes to the pathogenesis of PH. The complexity of this question is amplified by the myriad of cellular processes in which TGF beta participates and the multiple cell types (endothelial, smooth muscle, and adventitial fibroblasts) it is capable of affecting and which may influence the development of pulmonary hypertension. In order to begin addressing the molecular pathway, this project proposes to study the role of TGF beta signaling in endothelial cells. We will rely on an endothelial cell inducible deletion of TGF beta receptor II and the well-established hypoxic model of PH to demonstrate the role of endothelial cell TGF beta signaling in the development of PH. Endothelial-mesenchymal transition will be characterized by genetically tagging endothelial cells and following their fate after exposure to chronic hypoxia. Finally, we will demonstrate that TGF beta signaling is required for endothelial-mesenchymal transition and test a novel inhibitor of TGF beta mediated transition. Understanding the molecular mechanism by which this occurs can provide insight into the initiation of human PAH and the development of novel therapeutic targets.