Circulating biomarkers of IPAH.

儿童或成人肺动脉高压（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。血管扩张剂是 疗法然而，20-30%的患者对血管扩张剂没有反应，并且无反应者的预后较差。 预后最终需要肺移植。由于病理生物学未知，血管扩张剂治疗 显著的发病率和成本以及缺乏特异性诊断/预后生物标志物，我们的长期目标是 确定IPAH的循环、诊断和预后标志物，以改善长期结局。到 为了实现这一目标，我们优化了一种无偏见的，深入的蛋白质组学方法，用于肺结核患者。 高血压在我们使用IPAH儿童纵向血浆样本的初步数据中， 已经确定了IPAH患者中许多血浆蛋白的显著变化。所以我们 假设来自IPAH患者的血浆样品将含有诊断/预后肺， 内皮细胞特异性生物标志物。为了验证这一假设，我们将使用无偏见的蛋白质组学方法 鉴定来自肺，特别是肺动脉的独特循环PAH生物标志物蛋白 内皮细胞（PAEC）。在目标1中。使用最先进的定量生物标志物开发管道，我们 将通过比较IPAH的蛋白质组来鉴定循环肺，特别是IPAH的PAEC特异性生物标志物， 从移植用于IPAH的PHBI Repository患者（n=10）中收获的匹配血浆、肺和PAEC，或 与先天性心脏病相关的APAH（n = 10）和正常非移植供体（n = 10）， 对照在目标2中。我们将使用高通量定量方法验证候选血浆IPAH生物标志物， 使用剩余的PHBI储存库进行基于MS的多重反应监测（MRM）测定 血浆样本，以验证蛋白质鉴定，它的疗效在儿童和成人，并确定它的 IPAH与非IPAH的特异性。创新之处在于，该提案采用了最先进的无偏见 蛋白质组学发现管道到一组新的匹配PAH和正常血液，肺和PAEC，以确定 诊断/预后IPAH生物标志物。这些方法将首次允许特定的潜在的 IPAH和可能的PAH的肺部生物标志物为未来的临床试验提供了丰富的新数据 和开发新的治疗靶点。重要的是，尽管在这方面取得了进展， IPAH的治疗和生存率，病因仍在很大程度上未知。此外，我们缺乏 诊断/预后意味着容易和准确地识别对治疗无反应的患者。 因此，生物标志物可以填补这一空白，提供适当降低治疗发病率的手段 逐步升级治疗，并作为衡量新疗法的标准。

Pulmonary artery hypertension in children or adults (PAH) is a progressive and fatal disease characterized by sustained elevations of pulmonary artery pressure of unknown etiology. Vasodilators are the mainstay of therapy. However 20-30% of patients do not respond to vasodilators and non-responders have a poor prognosis eventually requiring lung transplantation. As the pathobiology is unknown, vasodilator therapy has significant morbidity and cost and specific diagnostic/prognostic biomarkers are lacking, our long-term goal is to identify circulating, diagnostic and prognostic markers of IPAH to improve long term outcomes. To pursue this goal, we have optimized a non-biased, in-depth proteomics approach in patients with pulmonary hypertension. In our preliminary data using longitudinal plasma samples of children with IPAH we have already identified significant changes in a number of plasma proteins in patients with IPAH. Therefore, we hypothesize that plasma samples from patients with IPAH will contain diagnostic/prognostic lung and endothelial cell specific biomarkers. To examine this hypothesis we will use a non-biased proteomics approach to identify unique circulating PAH biomarker proteins from the lung and specifically pulmonary arterial endothelial cells (PAEC). In Aim 1. Using a state of the art quantitative biomarker development pipeline, we will identify circulating lung and in particular, PAEC specific biomarkers of IPAH by comparing proteomes of matched plasma, lung and PAEC harvested from PHBI Repository patients transplanted for IPAH (n=10) or APAH (n=10) related to congenital heart disease and (n=10) and normal non-transplanted donors (n=10) as controls. In Aim 2. we will verify candidate plasma IPAH biomarkers using high throughput quantitative multiplex MS-based (multple reaction montioring (MRM) assays using the remaining PHBI Repository of plasma samples to verify the protein identification, it's efficacy in both children and adults and determine it's specificity for IPAH vs non-IPAH. The innovation is that this proposal applies a state of the art unbiased proteomics discovery pipeline to a novel set of matched PAH and normal blood, lung and PAEC to identify diagnostic/prognostic IPAH biomarkers. These methods will allow for the first time the potential for specific lung biomarkers of IPAH and possibly PAH in general providing a wealth of new data for future clinical trials and development of new therapeutic targets. The significance is that although there have been advances in therapy and survival with IPAH, the etiology is still largely unknown. In addition we lack the diagnostic/prognostic means to easily and accurately identify patients that are unresponsive to therapy. Therefore biomarkers could fill this void providing the means to decrease therapeutic morbidity, appropriately escalate therapy and serve as measures to benchmark new therapies.