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 病因不明的肺动脉压持续升高。肺动脉平滑肌细胞 最终导致心力衰竭的PASMC（PASMC）和PAEC（PAEC）增殖是心力衰竭的关键组成部分。 肺动脉高压病理生理反应。我们目前的诊断/预后技术水平 （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，诊断性较差 相关性，被全身性疾病混淆，不适用于所有年龄。我们现在有试验数据， IGFBP失调是PAH严重程度和生存率的重要循环预测因子。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作用，以及作为一种潜在的 循环PAH治疗反应和存活的新测量。建议的意义 研究表明，通过将IGF途径的失调与肺内皮/平滑肌细胞 增殖、患者存活率和对治疗的反应，揭示了PAH病理生物学的关键机制 并为PAH的新治疗、诊断和预后策略提供了基础。使用可用 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PAEC 和PASMC从PHBI，我们的总体目标将在以下具体目标解决：1）确定， IGF和IGFBPs是儿童和成人PAH严重程度、生存率和治疗反应的预测因子。（二） 确定与IGFs和IGFBPs循环水平相关的遗传变异及其与临床的关系 严重性和生存率。3)确定IGFBPs对肺肿瘤表型反应的贡献 来自PAH和正常供体的血管细胞（PAEC和PASMC）。如果在本研究中得到验证， IGF途径可以填补临床护理的重要空白，并作为一个新的机会， 了解PAH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.