Role of the PDGF signaling pathway in pulmonary artery hypertension

PDGF信号通路在肺动脉高压中的作用

基本信息

批准号：
8714040
负责人：
Akiko Hata
金额：
$ 38.67万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8714040
关键词：
Animal Model Antisense Oligonucleotides Bone Morphogenetic Proteins Chronic Clinical Combined Modality Therapy Data Development Diagnosis Disease Down-Regulation Experimental Animal Model Functional RNA Genes Goals Human Hypertension Hypoxia Imatinib mesylate Injection of therapeutic agent Left Lesion Lung Medial Mediating Messenger RNA MicroRNAs Molecular Monocrotaline Mus Mutation Oligonucleotides Pathogenesis Pathway interactions Patients Penetrance Phenotype Platelet-Derived Growth Factor Platelet-Derived Growth Factor Receptor Preventive Intervention Proteins Pulmonary artery structure Rattus Regulation Resistance Rodent Role SU 5416 Signal Pathway Signal Transduction Smooth Muscle Myocytes Survival Rate Terminal Disease Testing Therapeutic Intervention Time Transducers Vascular Endothelial Growth Factor Receptor Vascular remodeling base bone morphogenetic protein receptor type II cohort efficacy testing migration mouse model new therapeutic target novel osteogenin prevent public health relevance pulmonary arterial hypertension

项目摘要

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.

描述（由申请人提供）：肺动脉高血压（PAH）是一种疾病，其特征是与肺血管重塑相关的肺动脉抗性（PA）耐药性，包括肺动脉平滑肌细胞的增殖（PASMC）和丛生形成。编码骨形态发生蛋白（BMP）II型受体（BMPRII）的基因突变与PAH（4-6）有关，但是BMPRII突变的渗透限制为〜20％，表明还有其他因素有助于PAH的发展。在PAH患者的重塑肺动脉（PAS）的内侧层中鉴定出血小板衍生的生长因子（PDGF）信号通路的异常表达和激活，并通过单蛋白（MCT）或缺氧治疗的啮齿动物进行了重塑。给药PDGF受体（伊马替尼麦甲酸酯）的拮抗剂可逆转PA动物模型中的PA重塑以及PAH患者的临床改善。我们先前证明了PDGF信号拮抗肺动脉平滑肌细胞（PASMC）中的BMP信号通路，并促进了“合成”表型，其特征是增殖，迁移和收缩力降低。我们将Tribbles同源性3（TRB3）确定为蛋白质与BMPRII的羧基末端结构域相互作用，对于BMP信号通路必不可少。我们鉴定了一个小的非编码microRNA-24（miR-24），该MirORNA-24（miR-24）在PASMC中用pDGF刺激而受到有效诱导。 miR-24的表达增加导致TRB3 mRNA的降解，因此BMP-SMAD信号促进了从收缩物到合成表型的转换。 miR-24的抑制可防止BMP-SMAD信号的下调和PDGF的表型切换）。该应用的目的是阐明PDGF介导的miR-24诱导有助于PAH的发病机理的机制。要测试的中心假设是PDGF-MIR-24轴的扰动抑制PA重塑，并通过增加TRB3和BMP信号通路来介导PA的临床改善。在SA1中，我们将检查PDGF介导的TRB3调节的扰动的功效。在SA2中，我们将测试miR-24在PAH动物模型中扰动的疗效。最后，SA3将证明在人PAH患者中对miR-24的放松管制，并确定miR-24的新靶标。