# Molecular regulation of BMPRII stability in lung fibrosis

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2024 · $513,678

## Abstract

Abstract
Idiopathic Pulmonary Fibrosis (IPF) is a chronic, irreversible, aging-associated, and ultimately fatal lung disease.
The median survival of pulmonary fibrosis patients is only 4-5 years. There is no treatment to reverse fibrosis
and cure IPF. Development of anti-fibrotic therapeutics is an unmet need in the treatment of IPF. The relentless
progression of IPF is due in part to the failure of fibrosis resolution. The development of therapies for IPF relies
on the comprehensive understanding of fibrosis resolution pathways. Accumulating evidence shows that
activation of BMPs signaling induces myofibroblast de-differentiation and fibrosis resolution. A key receptor, BMP
receptor II (BMPRII), in BMPs signaling has been shown to be reduced in fibrotic lungs; thus, restoration of
BMPRII in fibrotic lungs is a potential therapy to treat IPF. However, molecular regulation of BMPRII stability has
not been well studied. In our preliminary data, we discovered that (i) BMPRII is degraded in the lysosome system
in response to TGF-β1 and lipid peroxidation inducers, which play critical roles in the development of lung fibrosis;
(ii) Nedd4L stabilizes BMPRII; (iii) downregulation of Nedd4L reduced BMP4 signaling and the effects were
rescued by overexpression of BMPRII; (iv) overexpression of Nedd4L promoted de-differentiation of lung
myofibroblasts. Based on these novel observations, we hypothesized that Nedd4L promotes BMPRII stability
and facilitates BMPs/BMPRII-mediated myofibroblast de-differentiation and pulmonary fibrosis resolution. We
propose three Specific Aims to evaluate our hypothesis. First, we will determine the regulatory mechanisms by
which Nedd4L stabilizes BMPRII. We will identify the ubiquitination and Nedd4L docking sites on BMPRII and
determine the effect of Nedd4L-mediated K63-linked ubiquitination on BMPRII internalization and stability. Next,
we will determine if Nedd4L suppression is essential for TGF-β1- and lipid peroxidation-induced BMPRII
degradation. Finally, we will determine if Nedd4L facilitates lung fibrosis resolution through stabilization of
BMPRII and promotion of BMPs-mediated myofibroblast de-differentiation and inactivation. We will determine if
elevated BMPRII stability by Nedd4L facilitates myofibroblast de-differentiation in ex-vivo cultured lung
myofibroblasts. An inducible fibroblast specific Nedd4L depletion mouse will be used in both resolving and non-
resolving lung fibrosis models. The proposed studies will address key knowledge gaps regarding molecular
regulation of BMPRII stability and anti-fibrotic effects of BMPs/BMPRII. Success of the proposed studies will
suggest that targeting Nedd4L/BMPRII to rescue BMPRII expression in fibrotic lungs may lead to new
opportunities to halt pro-fibrotic progression and promote fibrosis resolution.

## Key facts

- **NIH application ID:** 10908364
- **Project number:** 5R01HL169203-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Yutong Zhao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $513,678
- **Award type:** 5
- **Project period:** 2023-09-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908364

## Citation

> US National Institutes of Health, RePORTER application 10908364, Molecular regulation of BMPRII stability in lung fibrosis (5R01HL169203-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10908364. Licensed CC0.

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