Role of miR125 in pulmonary hypertension secondary to interstitial lung disease

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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.