Role of IGF axis in pulmonary hypertension

项目摘要 儿童或成人的肺动脉高压(PAH)是一种进行性和致命性疾病，其特征是 原因不明的持续的肺动脉压升高。肺动脉平滑肌细胞 (PASMC)和血管内皮细胞(PAEC)的增殖最终导致心力衰竭是 肺动脉高压的病理生理反应。我们目前的诊断/预后状态 (超声心动图、6分钟步行试验和NTproBNP水平)不具有肺/血管特异性，诊断能力较差 相关性，被系统性疾病混淆，并不适用于所有年龄段。我们现在有了试点数据， IGFBP失调是预测PAH严重程度和存活率的重要循环指标。这个项目的总体目标是 建议阐明IGF轴在PAH中的体外和体内机制以及作为一种潜在的 循环新的PAH治疗反应和生存指标。建议的重要意义 研究表明，通过将IGF途径的失调与肺内皮细胞/平滑肌细胞联系起来 增殖、患者存活和治疗反应，揭示了PAH病理生物学的关键机制 为PAH的新的治疗、诊断和预后策略提供了基础。使用可用的 儿科(科罗拉多大学)、成人(范德比尔特)和多中心(PAHBiobank)队列和孤立的PAEC PHBI和PASMC，我们的总体目标将在以下具体目标中解决：1)确定是否 IGF和IGFBPs是预测儿童和成人PAH严重程度、存活率和治疗反应的指标。2) 确定与IGF和IGFBPs循环水平相关的遗传变异及其与临床的关系 严重性和存活率。3)确定IGFBPs对肺组织表型反应的贡献 来自PAH和正常供体的血管细胞(PAEC和PASMC)。如果这项研究证实了这一点，那么 IGF途径可以填补临床护理中的一个重要空白，并为更彻底的 了解PAH的病理生物学和开发新的治疗靶点。

Project Summary Pulmonary arterial hypertension (PAH) in children or adults is a progressive and fatal disease characterized by sustained elevations of pulmonary artery pressure of unknown etiology. Pulmonary arterial smooth muscle cell (PASMC) and endothelial (PAEC) proliferation that ultimately lead to heart failure are key components of the pulmonary hypertension pathophysiologic response. Our current diagnostic/prognostic state of art (echocardiography, 6 minute walk test and NTproBNP levels) are not lung/vascular specific, have poor diagnostic correlation, confounded by systemic diseases and are not applicable to all ages. We now have pilot data that IGFBP dysregulation is a significant circulating predictor of PAH severity and survival. The overall goal of this proposal is to elucidate the in vitro and in vivo mechanistic role of IGF axis in PAH and potential as a circulating new measure of PAH therapeutic response and survival. The significance of the proposed studies is that by linking dysregulation of the IGF pathway to pulmonary endothelial/smooth muscle cellular proliferation, patient survival, and response to treatment, a critical mechanism of PAH pathobiology is revealed and provides the basis for new therapeutic, diagnostic and prognostic strategies in PAH. Using available pediatric (University of Colorado), adult (Vanderbilt) and multicenter (PAHBiobank) cohorts and isolated PAEC and PASMC from the PHBI, our overall goal will be addressed in the following specific aims: 1) Determine if IGF and IGFBPs are PAH predictors of severity, survival and response to therapy in children and adults. 2) Identify genetic variants associated with circulating levels of IGFs and IGFBPs and their relationship with clinical severity and survival. 3) Defining the contribution of the IGFBPs to the phenotypic responses of pulmonary vascular cells (PAEC and PASMC) from PAH and normal donors. If validated in this study, dysregulation of the IGF pathway could fill an important gap in clinical care and serve as a new opportunity for a more thorough understanding of PAH pathobiology and development of new therapeutic targets.