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: 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
• 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

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）是一种肺血管疾病，其特征是肺血管重塑， 和死亡。最常见的pH形式之一是继发于间质性肺疾病（第3.2组）， 肺纤维化（PF）患者的患病率约为30-40％。继发于PF的pH发展增加 死亡率约3倍，因为疾病的综合疾病对大多数疗法是难治性的。缺乏有效的疗法 至少部分归因于缺乏PF-PH的临床前模型。我们已经开发了 新型的临床前大鼠模型合并的PF-PH概括了大多数病理生理学的发现 PF-PH患者。我们还确定了一种新型microRNA，mir125b-3p（mir125b），优先 与单独的PF相比，在PF-PH的大鼠和人类的肺中显着上调。 miR125上调与其目标TNFAIP3的显着下调有关，从而增加 Slug的表达，SLUG是一种转录因子，负责促进内皮到间充质转变 （ENDMT）。我们的初步数据显示，先前存在的PF的MiR125b的过表达是 足以在体外诱导pH值并促进人类肺动脉内皮细胞（HPAEC）的EndMT。 该提案的目的是确定miR125如何诱导肺血管重塑和末端 在预先存在的PF中促进pH，并研究靶向miR125和snai2的治疗潜力 防止pH中存在的PF。我们的中心假设是：1）肺中miR125b的明显增加 通过降低其靶标TNFAIP3的表达来促进PF向PF-PH的过渡，从而导致SNAI2 刺激EndMT的上调导致肺血管重塑恶化； 2）击倒 具有预先存在的PF的大鼠肺中的miR125b和/或sl可阻止从PF到PF-PH的过渡。目标1意志 通过在促进血管重塑促进pH中的MiR125b/slug轴的作用中获得机械洞察力 大鼠/患者患有PF的患者； AIM 2将获得有关miR125b/slug轴作用的机械洞察力 通过驾驶EndMT促进pH，在患有PF的大鼠/患者中促进pH； AIM 3将检查Mir125b是否 和/或SLUG可以用作新的治疗靶标，以防止PF向PF-PH过渡。提出的研究 将对MiR125过表达诱导的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的新型治疗策略。