Discovery of biomarkers of pulmonary hypertension

描述(由申请人提供)：本R21提案的目标是提供有关噬菌体展示的新应用的初步数据，旨在揭示与在重建的肺动脉中原位发现的那些一致的严重肺动脉高压(SPH)的血清标志物。SPH是一种不可逆的恶性肺动脉压升高，通常与右侧心力衰竭的高死亡率相关。诊断的延迟对目前可用的几种治疗方案的反应有限。识别该病的生物标志物将大大有助于SPH的早期诊断和监测治疗反应。我们推测，SPH患者的血清中存在与SPH的肺动脉重塑相关的血管标志物，这些标志物从肺血管系统中脱落，并在患者的血清中表达。我们建议使用噬菌体展示方法来发现这些独特的组织和血清疾病标志物。 该建议依赖于PI储存的SPH患者的人类肺组织，以及霍普金斯计划在基因组应用中储存的血液样本，或者是在本研究过程中收集的血液样本。 我们提出了两个目标：1.使用最先进的激光显微切割肺组织的平滑肌或内皮细胞样本，利用噬菌体展示技术确定SPH的内皮细胞或平滑肌表型标志物；2.利用PPH血清配体的噬菌体展示技术，确定SPH患者与轻度PH患者或对照组相比所特有的血清标志物，这些血清标志物也出现在重塑的肺动脉中。 我们相信，我们的建议满足了指导R21奖项的关键要求，因为它是创新的，它可能对SPH的诊断和治疗以及旨在寻找其他肺部疾病标记物(如间质性肺疾病或结节病)的新方法产生潜在的高度影响，并可能导致肺部疾病病理生物学研究的新场所。

DESCRIPTION (provided by applicant): The goal of this R21 proposal is to provide preliminary data on a novel application of phage display aimed at uncovering serum markers of severe pulmonary hypertension (SPH) that are concordant with those identified in situ in remodeled pulmonary arteries. SPH is an irreversible, malignant elevation of pulmonary artery pressures, often associated with high mortality due to right side heart failure. The delay in diagnosis imparts limited response to a handful of therapeutic options presently available. Identification of biomarkers of the disease would significantly aid in early diagnosis of SPH and to monitor therapeutic responses. We hypothesize that vascular markers unique to pulmonary artery remodeling in SPH, shed from the pulmonary vasculature and are represented in the serum of patients with SPH. We propose to uncover these unique tissue and serum disease markers using phage display methodology. The proposal relies on human lung tissue of patients with SPH banked by the PI and on blood samples either banked by the Hopkins Program in Genomics Application or to be collected throughout the course of the present study. Two aims are proposed: 1. To define endothelial cell or smooth muscle phenotypic markers of SPH using phage display, using state of the art laser micro-dissected smooth muscle or endothelial cell samples of PPH lungs; and 2. To define serum markers unique to patients with SPH, as compared to mild PH or control patients, which are also represented in the remodeled pulmonary arteries, using phage display of PPH serum ligands. We believe that our proposal fulfils the critical requirements that guide the R21 award in that it is innovative, it may have a potential high impact in the diagnosis and management of SPH and on novel approaches aimed at finding markers of other lung diseases, such as interstitial lung diseases or sarcoidosis, and may lead to novel venues of investigation of pathobiology of lung disease.