# The Impaired FRNK in IPF

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2024 · $539,434

## Abstract

ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease with no effective treatment. The
biological processes that underlie the persistent fibrotic repair and their molecular drivers have
yet to be fully elucidated. Focal adhesion kinase (FAK)-Related Non-Kinase (FRNK) acts as an
endogenous brake on lung fibrosis. FRNK is downregulated in IPF lung tissues and IPF
fibroblasts, and the extent of FRNK downregulation tightly correlates with rapidity of motility in
IPF fibroblasts. FRNK inhibits myofibroblast differentiation. Importantly, FRNK deficiency
exacerbates lung fibrosis in bleomycin-challenged mice. However, the underlying mechanism
whereby FRNK downregulation drives fibrotic responses remains unknown. Talin plays a critical
role in mechano-transduction and cell contraction through its links between integrins and cellular
contraction machinery; therefore, this link functions as the ‘Mechano-Joint’ of Talin. Our
preliminary data demonstrate that Talin plays an important role in myofibroblast survival through
its ‘Mechano-Joint’. Talin is activated in response to transforming growth factor beta-1 (TGF-β1)
and Talin downregulation induces myofibroblasts apoptosis. FRNK induces Talin cleavage and
myofibroblast apoptosis. We hypothesize that FRNK induces myofibroblast apoptosis through
disruption of ‘Mechano-Joint’ of Talin. Preliminary data show that FRNK downregulation
promotes activation of Crk-associated substrate (Cas) and S100A4 expression, which
contributes to an invasive fibroblast phenotype. Furthermore, preliminary data support that KH-
type splicing regulatory protein (KSRP) promotes rapid FRNK mRNA decay, resulting in FRNK
downregulation in IPF. We hypothesize that pathologic FRNK downregulation by KSRP
orchestrates cooperative fibrotic signaling mediated by Talin, Cas, and S100A4, resulting in
persistent fibrotic responses in IPF. Aim 1 will define the novel role of ‘Mechano-Joint’ of Talin in
myofibroblast survival, and to examine the effects of gain of FRNK in myofibroblast on lung
fibrosis in vivo. Aim 2 will determine the mechanism whereby impaired FRNK function increases
Cas activation and S100A4 expression, and to examine the effect of gain of FRNK in S100A4-
expressing cells, on fibrogenesis. Aim 3 will determine the mechanism whereby KSRP regulate
FRNK function. These studies will support our long-term goal to utilize knowledge gained from
these studies to develop novel therapeutic approaches for IPF in humans.

## Key facts

- **NIH application ID:** 10842265
- **Project number:** 5R01HL152183-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** QIANG DING
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $539,434
- **Award type:** 5
- **Project period:** 2021-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842265

## Citation

> US National Institutes of Health, RePORTER application 10842265, The Impaired FRNK in IPF (5R01HL152183-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10842265. Licensed CC0.

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