胞外基质蛋白Periostin调控胶原受体DDR2在低氧性肺动脉高压肺血管重构中的作用及机制研究

Pulmonary hypertension is a life-threatening disease, and its pathogenesis is poorly defined. We early detected the abnormal expression of a extracellular matrix protein-Periostin in pulmonary arteries from patients with pulmonary hypertension. We also found that Periostin regulates the vascular remodeling of pulmonary hypertension by binding to discoidin domain receptor 2 (DDR2), which was related to the activation of transcription factor FOXA1. We will utilize cDNA array, gene transfection, molecular biology approaches to systematically explore the regulation of Periostin on DDR2-mediated FOXA1 activation in PAH. We will further elucidate the interaction of Periostin-DDR2 in activating the expression of FOXA1 and possible molecular mechanism involved in pulmonary vascular remodeling with PAH. We expect to expand the understanding the mechanism of the occurrence of vascular remodeling in hypoxic PAH and further provide an effective therapeutics target to be considered in the clinical management of PAH.

肺动脉高压是一种极度恶性疾病，病因未明。前期我们通过抗体芯片技术在肺动脉高压病人肺血管中检测到胞外基质蛋白-成骨细胞特异因子-2(Periostin)高表达，并发现Periostin通过特异性结合盘状结构域受体2(DDR2)调控肺动脉高压血管重构。进一步研究发现这一过程与转录因子FOXA1活化有关。拟通过基因芯片、基因转染、分子生物学等技术，系统研究Periostin调控DDR2以及FOXA1介导PAH，同时阐明Periostin-DDR2如何相互调控FOXA1的表达以及影响肺血管重构的分子机制。本项目的实施有助于揭示缺氧肺动脉高压的分子机制，有望为该致死性疾病的诊断和治疗提供新的靶标。

本课题通过研究胞外基质蛋白Periostin在肺动脉高压发病机制中的作用探讨了肺动脉高压发病的分子机制。主要结果：（1）Periostin在肺动脉高压病人肺血管中表达明显上调，进一步基于肺组织以及血清学的样本检测发现Periostin同肺动脉高压临床进展程度及肺动脉压力呈正相关，为临床准确判断肺动脉高压的发展及预后提供了很好的监测指标，具有极为重要的临床意义；（2）Periostin基因敲除可明显抑制缺氧及SU5416联合慢性缺氧诱导的小鼠肺动脉高压血管重构；特殊修饰的Periostin siRNA寡核苷酸药物对肺动脉高压具有明显的治疗作用；（3）Periostin调控肺动脉内皮细胞的增殖、迁移和小管形成；肺动脉内皮细胞分泌的Periostin介导平滑肌细胞增殖及迁移；（4）Periostin可以与HIF-1α形成正反馈调节，促进TrkB的表达，抑制BMPR2，从而上调VEGF, ET-1的表达，导致肺动脉高压的发生。这些结果提示，Periostin是调控缺氧性肺动脉高压形成的重要靶分子。