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

• 批准号: 9917602
• 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
• 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/9917602
• 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; 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 therapeutics; outcome forecast; overexpression; pre-clinical; prevent; pulmonary artery endothelial cell; slug; targeted treatment; therapy development; transcription factor; transcriptome sequencing

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.

项目摘要 肺动脉高压(PH)是一种以肺血管重构为特征的肺血管疾病， 和死亡。肺高压最常见的形式之一是继发于间质性肺疾病(第3.2组)。 在肺纤维化(PF)患者中的患病率约为30-40%。次于PF的PH值发展增加 死亡率约为3倍，因为这种合并疾病对大多数治疗方法都难以奏效。缺乏有效的疗法 至少在一定程度上，可以归因于缺乏相关的PF-PH临床前模型。我们已经开发出一种 一种新的联合PF-PH的临床前大鼠模型，它概括了在 PF-PH患者。我们还鉴定了一个新的microRNA，miR125b-3p(MiR125b)，它优先于 与单独使用PF相比，PF-PH联合用药大鼠和人的肺组织表达显著上调。 MiR125上调与其靶标TNFAIP3的显著下调相关，导致 促进内皮细胞向间充质转化的转录因子Slug的表达 (完)我们的初步数据显示，预先存在PF的大鼠肺组织中miR125b过表达。 足以在体外诱导人肺动脉内皮细胞(HPAECs)的PH和促进EndMT。 这项建议的目标是确定miR125如何诱导肺血管重构和EndMT 在已存在的PF中促进PH，并研究靶向miR125和SNAI2的治疗潜力。 预防预先存在的PF中的PH。我们的中心假设是：1)肺中miR125b显著增加 通过降低其靶基因TNFAIP3的表达促进PF向PF-PH的转化，从而导致SNAI2 上调刺激EndMT，导致肺血管重塑恶化；2)下调 在预先存在PF的大鼠的肺中，miR125b和/或鼻涕虫可阻止从PF向PF-PH的转变。目标1将 了解miR125b/Slug轴通过推动血管重塑在促进高血压中的作用 已经存在PF的大鼠/患者；Aim 2将获得对miR125b/Slug轴在 通过驱动EndMT促进既往存在PF的大鼠/患者的PH；目标3将检查miR125b 和/或鼻塞可作为防止PF向PF-PH转变的新的治疗靶点。建议进行的研究 将为miR125过表达诱导PH的机制提供重要的见解，从而使我们能够 靶向miR125和/或段塞作为预防PH的新治疗策略。