Circulating biomarkers of IPAH.

描述（由申请人提供）：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。血管扩张剂是主要的治疗方法。然而，20-30%的患者对血管扩张剂无反应，无反应者预后差，最终需要肺移植。由于病理生物学尚不清楚，血管扩张剂治疗具有显著的发病率和成本，并且缺乏特异性的诊断/预后生物标志物，我们的长期目标是确定循环、诊断和预后标志物，以改善IPAH的长期预后。为了实现这一目标，我们在肺动脉高压患者中优化了一种无偏见的、深入的蛋白质组学方法。在我们使用IPAH儿童纵向血浆样本的初步数据中，我们已经发现IPAH患者血浆蛋白的一些显著变化。因此，我们假设IPAH患者的血浆样本将包含诊断/预后的肺和内皮细胞特异性生物标志物。为了验证这一假设，我们将使用无偏差的蛋白质组学方法从肺部，特别是肺动脉内皮细胞（PAEC）中鉴定独特的循环多环芳烃生物标志物蛋白。在目标1中。利用最先进的定量生物标志物开发管道，我们将通过比较PHBI Repository移植的与先天性心脏病相关的IPAH （n=10）或APAH （n=10）患者（n=10）和正常非移植供体（n=10）作为对照的匹配血浆、肺和PAEC的蛋白质组学，识别循环肺，特别是PAEC特异性IPAH的生物标志物。在目标2中。我们将使用高通量定量多重MS-based多反应监测（MRM）方法验证候选血浆IPAH生物标志物，使用剩余的PHBI血浆样本库验证蛋白质鉴定，它对儿童和成人的有效性，并确定它对IPAH与非IPAH的特异性。创新之处在于，该提案将最先进的无偏见蛋白质组学发现管道应用于一组新的匹配PAH和正常血液，肺和PAEC，以识别诊断/预后IPAH生物标志物。这些方法将首次发现IPAH特异性肺生物标志物的潜力，并可能在一般情况下为未来的临床试验和开发新的治疗靶点提供丰富的新数据。重要的是，尽管IPAH的治疗和生存率已经取得了进展，但其病因仍在很大程度上是未知的。此外，我们缺乏诊断/预后手段来轻松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，提供降低治疗发病率的手段，适当地升级治疗，并作为基准新疗法的措施。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Pulmonary artery hypertension in children or adults (PAH) is a progressive and fatal disease and although there have been advances in therapy and survival with IPAH, the etiology is still largely unknown. In this proposal we will use a state of the art proteomics pipeline to identify and verify specific lung/pulmonary artery endothelial cell prognostic/diagnostic IPAH biomarkers. Therefore biomarkers could fill this void providing the means to decrease therapeutic morbidity, appropriately escalate therapy and serve as measures to benchmark new therapies. (End of Abstract).