Role of the PDGF signaling pathway in pulmonary artery hypertension

描述（由申请人提供）：肺动脉高压（PAH）是一种以肺动脉（PA）阻力增加为特征的疾病，与肺血管重塑相关，包括肺动脉平滑肌细胞（PASMC）增殖和丛状结构形成。编码骨形态发生蛋白（BMP）II型受体（BMPRII）的基因突变与PAH相关（4-6），但BMPRII突变的发生率仅限于~ 20%，表明还有其他因素导致PAH的发生。在接受野百合碱（MCT）或缺氧治疗的PAH患者和啮齿动物的重塑肺动脉（PA）中层中发现血小板衍生生长因子（PDGF）信号通路的异常表达和激活。PDGF受体拮抗剂（甲磺酸伊马替尼）的给药逆转了PAH动物模型中的PA重塑以及PAH患者的临床改善。我们以前证明，PDGF信号拮抗肺动脉平滑肌细胞（PASMCs）中的BMP信号通路，并促进以增殖增加、迁移和收缩性降低为特征的“合成”表型。我们确定了Tribbles同源3（Trb 3）作为一种蛋白质与BMPRII的羧基末端结构域相互作用，并对BMP信号通路至关重要。我们鉴定了一种小的非编码microRNA-24（miR-24），其在PASMC中用PDGF刺激时被有效诱导，并靶向Trb 3。miR-24的表达增加导致Trb 3 mRNA的降解，因此BMP-Smad信号促进从收缩表型到合成表型的转换。miR- 24的抑制防止BMP-Smad信号传导的下调和PDGF的表型转换）。本申请的目的是阐明PDGF介导的miR-24诱导参与PAH发病机制的机制。待检验的中心假设是PDGF-miR-24轴的扰动抑制PA重塑并通过增强Trb 3和BMP信号传导途径介导PAH表型的临床改善。在SA 1中，我们将检查扰动PDGF介导的Trb 3调节的功效。在SA 2中，我们将在PAH动物模型中检测miR-24干扰的疗效。最后，SA 3将证明人类PAH患者中miR-24的失调，并确定miR-24的新靶点。

DESCRIPTION (provided by applicant): Pulmonary artery hypertension (PAH) is a disease characterized by increased pulmonary artery (PA) resistance associated with pulmonary vascular remodeling, including proliferation of pulmonary artery smooth muscle cells (PASMCs) and formation of plexiform. Mutations in the gene encoding the bone morphogenetic protein (BMP) type II receptor (BMPRII) are associated with PAH(4-6), however a penetrance of BMPRII mutations is limited to ~20%, indicating that there are other factors contribute to the development of PAH. Aberrant expression and activation of the platelet derived growth factor (PDGF) signaling pathway are identified in the medial layer of the remodeled pulmonary arteries (PAs) from PAH patients and rodents treated with monocrotaline (MCT) or hypoxia. Administration of an antagonist of the PDGF receptor (imatinib mesylate) reverses PA remodeling in PAH animal models as well as clinical improvements in PAH patients. We demonstrated previously that the PDGF signal antagonizes the BMP signaling pathway in pulmonary artery smooth muscle cells (PASMCs) and promotes the "synthetic" phenotype characterized by increased proliferation, migration, and reduced contractility. We identified Tribbles homology 3 (Trb3) as a protein interacts with the carboxyl-terminus domain of BMPRII and essential for the BMP signaling pathway. We identified a small non-coding microRNA-24 (miR-24) which is potently induced upon stimulation with PDGF in PASMCs and targets Trb3. Increased expression of miR-24 leads to a degradation of Trb3 mRNA, hence the BMP-Smad signal, which promotes a switch from the contractile to the synthetic phenotype. Inhibition of miR- 24 prevents downregulation of the BMP-Smad signaling and the phenotype switch by PDGF). The objective of this application is to elucidate the mechanism that the PDGF-mediated induction of miR-24 contributes to the pathogenesis of PAH. The central hypothesis to be tested is that perturbation of the PDGF-miR-24 axis inhibits PA remodeling and mediates clinical improvement of the PAH phenotype through augmenting Trb3 and the BMP signaling pathway. In SA1, we will examine the efficacy of perturbation of the PDGF-mediated Trb3 regulation. In SA2, we will test the efficacy of perturbation of miR-24 in animal models of PAH. Finally, SA3 will demonstrate the deregulation of miR-24 in human PAH patients and identify novel targets of miR-24.