# Role of miR125 in pulmonary hypertension secondary to interstitial lung disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $474,894

## Abstract

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.

## Key facts

- **NIH application ID:** 10312768
- **Project number:** 5R01HL147586-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Mansoureh Eghbali
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $474,894
- **Award type:** 5
- **Project period:** 2019-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10312768

## Citation

> US National Institutes of Health, RePORTER application 10312768, Role of miR125 in pulmonary hypertension secondary to interstitial lung disease (5R01HL147586-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10312768. Licensed CC0.

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