Role of miR125 in pulmonary hypertension secondary to interstitial lung disease

miR125在间质性肺疾病继发性肺动脉高压中的作用

基本信息

批准号：
10063562
负责人：
Mansoureh Eghbali
金额：
$ 47.49万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063562
关键词：
Automobile Driving Blood Vessels Cells Cessation of life Data Development Disease Down-Regulation Endothelium Genes Goals Histologic Human In Vitro Interstitial Lung Diseases Lung Lung Transplantation Lung diseases Mediating Mesenchymal MicroRNAs Modeling Molecular Mus Patients Pharmaceutical Preparations Phenotype Pre-Clinical Model Prevalence Prognosis Pulmonary Fibrosis Pulmonary Hypertension Pulmonary Vascular Resistance Rattus Refractory Role Secondary to Therapeutic Up-Regulation Vascular Diseases Vascular Endothelium Vascular Proliferation Vascular remodeling cell type effective therapy in vivo insight knock-down mortality new therapeutic target novel novel therapeutic intervention overexpression pre-clinical prevent pulmonary artery endothelial cell slug targeted treatment therapy development transcription factor transcriptome sequencing

项目摘要

Project Summary Pulmonary hypertension (PH) is a pulmonary vascular disease characterized by pulmonary vascular remodeling, and death. One of the most common forms of PH is secondary to interstitial lung disease (group 3.2) with a prevalence of about 30-40% in patients with pulmonary fibrosis (PF). PH development secondary to PF increases mortality about 3-fold as the combined disease is refractory to most therapies. The lack of effective therapies can be attributed, at least in part, to the lack of a relevant pre-clinical model of PF-PH. We have developed a novel pre-clinical rat model of combined PF-PH that recapitulates most of the pathophysiologic findings seen in patients with PF-PH. We have also identified a novel microRNA, miR125b-3p (miR125b), which is preferentially and significantly upregulated in the lungs of rats and humans with combined PF-PH compared to PF alone. miR125 upregulation is associated with significant downregulation of its target TNFAIP3 leading to increased expression of Slug, a transcription factor responsible for promoting endothelial to mesenchymal transition (EndMT). Our preliminary data shows overexpression of miR125b in the lungs of rat with pre-existing PF is sufficient to induce PH and to promote EndMT in human pulmonary artery endothelial cells (HPAECs) in vitro. The goal of this proposal is to determine how miR125 induces pulmonary vascular remodeling and EndMT to promote PH in pre-existing PF and to investigate the therapeutic potential of targeting miR125 and Snai2 in preventing PH in pre-existing PF. Our central hypotheses are: 1) marked increase of miR125b in the lungs promotes transition of PF to PF-PH by decreasing the expression of its target TNFAIP3 resulting in Snai2 upregulation that stimulates EndMT leading to worsening pulmonary vascular remodeling; and 2) Knock-down of miR125b and/or Slug in the lungs of rats with pre-existing PF prevents transition from PF to PF-PH. Aim 1 will gain mechanistic insights into the role of miR125b/Slug axis in promoting PH by driving vascular remodeling in rats/patients with pre-existing PF; Aim 2 will gain mechanistic insights into the role of miR125b/Slug axis in promoting PH by driving EndMT in rats/patients with pre-existing PF; and Aim 3 will examine whether miR125b and/or Slug can serve as novel therapeutic targets to prevent the transition of PF to PF-PH. The proposed studies will yield important insights into the mechanisms of miR125 overexpression induced PH, thus allowing us to target miR125 and/or Slug as novel therapeutic strategies to prevent PH.

项目概要肺动脉高压（PH）是一种以肺血管重塑为特征的肺血管疾病，和死亡。最常见的 PH 形式之一是继发于间质性肺疾病（组 3.2）肺纤维化（PF）患者的患病率约为30-40%。继发于 PF 增加的 PH 发展由于大多数疗法都难以治愈这种合并疾病，因此死亡率约为 3 倍。缺乏有效的治疗方法至少部分归因于缺乏相关的 PF-PH 临床前模型。我们开发了一个联合 PF-PH 的新型临床前大鼠模型，概括了 PF-PH 中的大部分病理生理学发现 PF-PH 患者。我们还鉴定了一种新的 microRNA，miR125b-3p (miR125b)，它优先与单独使用 PF 相比，联合使用 PF-PH 的大鼠和人类肺部的表达显着上调。 miR125 上调与其靶标 TNFAIP3 显着下调相关，从而导致 Slug 的表达，一种负责促进内皮细胞向间质细胞转化的转录因子（结束MT）。我们的初步数据显示，患有 PF 的大鼠肺部过度表达 miR125b 足以在体外诱导 PH 并促进人肺动脉内皮细胞 (HPAEC) 中的 EndMT。该提案的目标是确定 miR125 如何诱导肺血管重塑和 EndMT 促进已有 PF 的 PH 并研究靶向 miR125 和 Snai2 的治疗潜力预防已有 PF 中的 PH。我们的中心假设是：1）肺部 miR125b 显着增加通过降低其靶标 TNFAIP3 的表达（导致 Snai2）促进 PF 向 PF-PH 的转变刺激 EndMT 的上调导致肺血管重塑恶化； 2) 击倒预先存在 PF 的大鼠肺部中的 miR125b 和/或 Slug 可防止从 PF 向 PF-PH 的转变。目标1将通过驱动血管重塑，深入了解 miR125b/Slug 轴在促进 PH 中的作用已有 PF 的大鼠/患者；目标 2 将深入了解 miR125b/Slug 轴在通过驱动 EndMT 促进患有 PF 的大鼠/患者促进 PH；目标 3 将检查 miR125b 是否 Slug 和/或 Slug 可以作为新的治疗靶点来防止 PF 转变为 PF-PH。拟议的研究将对 miR125 过表达诱导 PH 的机制产生重要的见解，从而使我们能够靶向 miR125 和/或 Slug 作为预防 PH 的新治疗策略。