Role of miR125 in pulmonary hypertension secondary to interstitial lung disease

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， 与死PH最常见的形式之一是继发于间质性肺病（组3.2）， 在肺纤维化（PF）患者中的患病率约为30-40%。继发于PF升高的PH发展 死亡率约为3倍，因为大多数疗法对该组合疾病是难治的。缺乏有效的治疗 至少部分归因于缺乏PF-PH的相关临床前模型。 一种新型的PF-PH联合临床前大鼠模型，该模型重现了 我们还鉴定了一种新的microRNA，miR 125 b-3 p（miR 125 b）， 与单独PF相比，PF-PH联合给药的大鼠和人的肺中的表达显著上调。 miR 125上调与其靶点TNFAIP 3的显著下调相关，导致miR 125表达增加。 Slug的表达，Slug是一种负责促进内皮细胞向间质细胞转化的转录因子 （EndMT）.我们的初步数据显示，在预先存在PF的大鼠的肺中，miR 125 b的过表达是 足以在体外诱导PH并促进人肺动脉内皮细胞（HPAECs）中的EndMT。 该提案的目标是确定miR 125如何诱导肺血管重构和EndMT， 促进既存PF中的PH，并研究靶向miR 125和Snai 2在PF中的治疗潜力。 我们的中心假设是：1）肺中miR 125 b的显著增加 通过降低其靶点TNFAIP 3的表达促进PF向PF-PH的转变，导致Snai 2 刺激EndMT的上调导致肺血管重构恶化;和2）敲低 预先存在PF的大鼠肺中miR 125 b和/或Slug的表达阻止了PF向PF-PH的转变。 获得对miR 125 b/Slug轴通过驱动血管重构在促进PH中的作用的机制见解， 目的2将获得对miR 125 b/Slug轴在PF中的作用的机制见解。 通过驱动预先存在PF的大鼠/患者中的EndMT来促进PH;目标3将检查miR 125 b是否 和/或Slug可以作为新的治疗靶点，以防止PF转化为PF-PH。 将对miR 125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miR 125和/或Slug作为预防PH新治疗策略。

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.