Fibroblast Mediated Mechanisms of Pulmonary Hypertension

项目总结/摘要 肺动脉高压（PAH）的特征是毛细血管前肺动脉严重狭窄， 由于肌肉化增加和丛状病变的形成，导致动脉硬化。PAH有一个 高死亡率（1年死亡率为15%），仅在美国每年就导致约15，000例死亡。 BMPR2突变已在> 70%的遗传性PAH患者中鉴定， 散发性PAH;然而，基于这些发现，尚未开发出新的完全有效的治疗方法。 在拟议的研究中，我们将重点了解潜在的分子疾病机制，使用 表达遗传性PAH家族中发现的BMPR2突变的小鼠模型（BMPR2 +/R899X小鼠）。 基于令人兴奋的支持数据的主要焦点将是定义潜在的重要但神秘的角色 在BMPR2 +/R899X小鼠中，成纤维细胞作为疾病放大器。这一概念在很大程度上是由 在血管树周围的纤维化患者和动物模型中的观察， 纤维化肺病（例如特发性肺纤维化）也具有显著增加的 发展PAH。因此，根本的问题是， 肺成纤维细胞中BMPR2信号异常与PAH的发生和进展。在我的第一 作为一名独立的研究者，我将测试BMPR2 +/R899X成纤维细胞成为 被锁定在一个过度激活和致病的状态，这是至关重要的进展到暴发性疾病。到 为了验证这一假设，我将确定导致成纤维细胞异常活化的失调信号通路 包括BMPR2水平的降低如何导致激活素受体2A（ACVR2A）的异常激活。 此外，我将讨论成纤维细胞活化如何反过来导致血管平滑肌增殖， 从而导致PAH。针对先前的关切，我们彻底修改了提案， 提供新的数据，表明这项工作的可行性和潜在重要性。最终的目的是， 通过获得的见解，我们可以通过定义以前未知的方法将这些发现转化为新的疗法， 信号通路和抗PAH药物靶点。

PROJECT SUMMARY/ABSTRACT Pulmonary arterial hypertension (PAH) is characterized by a severe narrowing of pre-capillary pulmonary arteries due to a combination of increased muscularization and formation of plexiform lesions. PAH has a high mortality rate (15% 1-year mortality) resulting in ~15,000 deaths annually in the United States alone. Mutations in BMPR2 have been identified in >70% of patients with hereditary PAH and also some cases of sporadic PAH; however, no new and fully effective treatments have been developed based on these findings. In the proposed studies, we will focus on understanding the underlying molecular disease mechanisms using a mouse model that expresses a BMPR2 mutation found in a family with hereditary PAH (BMPR2+/R899X mice). The major focus based on exciting supporting data will be to define the potentially important but enigmatic role of fibroblasts as disease amplifiers in BMPR2+/R899X mice. This concept is driven in large measure by observations in patients and animal models of fibrosis localized around the vascular tree and that patients with fibrotic lung disease (such as idiopathic pulmonary fibrosis) also have significantly heightened likelihood of developing PAH. The fundamental question therefore is whether there is a causal relationship between aberrant BMPR2 signaling in pulmonary fibroblasts and the development and progression of PAH. In my first RO1 grant as an independent investigator I will test the hypothesis that BMPR2+/R899X fibroblasts become locked into a hyper-activated and pathogenic state that is crucial for the progression to fulminant disease. To test this hypothesis, I will identify the dysregulated signaling pathways that lead to aberrant fibroblast activation including how a reduction in BMPR2 levels leads to aberrant activation of Activin Receptor 2A (ACVR2A). Further, I will address how fibroblast activation in turn leads to vascular smooth muscle proliferation and thereby contributes to PAH. In response to the previous concerns we have thoroughly revised the proposal and provide new data showing feasibility and potential importance of the work. The intent ultimately will be that through the insights gained we can translate these findings into new therapies by defining previously unknown signaling pathways and anti-PAH drug targets.