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：
8461453
负责人：
Akiko Hata
金额：
$ 37.37万
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/8461453
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）：肺动脉高压（PAH）是一种以与肺血管重塑相关的肺动脉（PA）阻力增加为特征的疾病，包括肺动脉平滑肌细胞（PASMC）的增殖和丛状的形成。编码骨形态发生蛋白 (BMP) II 型受体 (BMPRII) 的基因突变与 PAH(4-6) 相关，但 BMPRII 突变的外显率仅限于约 20%，这表明还有其他因素导致 PAH(4-6) 的发生。多环芳烃的发展。在 PAH 患者和接受野百合碱 (MCT) 或缺氧治疗的啮齿动物的重塑肺动脉 (PA) 的内侧层中发现了血小板衍生生长因子 (PDGF) 信号通路的异常表达和激活。给予 PDGF 受体拮抗剂（甲磺酸伊马替尼）可逆转 PAH 动物模型中的 PA 重塑以及 PAH 患者的临床改善。我们之前证明，PDGF 信号拮抗肺动脉平滑肌细胞 (PASMC) 中的 BMP 信号通路，并促进以增殖、迁移增加和收缩性降低为特征的“合成”表型。我们鉴定出 Tribbles 同源 3 (Trb3) 是一种与 BMPRII 羧基末端结构域相互作用的蛋白质，并且是 BMP 信号通路所必需的。我们鉴定了一种小的非编码 microRNA-24 (miR-24)，它在 PASMC 中受到 PDGF 刺激后被有效诱导，并靶向 Trb3。 miR-24 表达增加导致 Trb3 mRNA 降解，从而产生 BMP-Smad 信号，促进从收缩表型向合成表型的转变。抑制 miR-24 可防止 BMP-Smad 信号传导的下调和 PDGF 引起的表型转换。本申请的目的是阐明 PDGF 介导的 miR-24 诱导导致 PAH 发病机制。待测试的中心假设是，PDGF-miR-24 轴的扰动会抑制 PA 重塑，并通过增强 Trb3 和 BMP 信号通路介导 PAH 表型的临床改善。在 SA1 中，我们将检查扰动 PDGF 介导的 Trb3 调节的功效。在 SA2 中，我们将测试 miR-24 扰动在 PAH 动物模型中的功效。最后，SA3 将证明人类 PAH 患者中 miR-24 的失调，并确定 miR-24 的新靶点。