# Role of Interferon Regulatory Factor 7 in Systemic Sclerosis Pathogenesis

> **NIH NIH R56** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2021 · $346,497

## Abstract

Abstract
Systemic sclerosis (SSc-scleroderma) is a multisystem autoimmune, fibrotic disease associated with high
morbidity and mortality. Progress in the development of effective therapies for SSc has been hampered by a
fragmented understanding of its pathogenesis. Although abundant evidence implicates dysregulated immunity
in SSc, the mechanisms by which the immune system influences fibroblast function are not well-understood.
We propose herein a multifaceted approach to elucidate the role of interferon regulatory factor 7 (IRF7) in
dermal fibroblasts as a pathologic bridge between immune dysregulation and fibrosis in SSc.
An interferon (IFN) gene expression signature is the most prominent peripheral blood cell transcript profile in
SSc. Moreover, our large-scale gene expression studies have identified IRF7, a key transcription factor in the
type I IFN pathway, as the top predicted upstream regulator of the SSc molecular profile in both skin and blood.
Our recently published work showed that IRF7 is significantly upregulated and activated in SSc skin and
explanted dermal fibroblasts, and that type I IFN upregulates IRF7 expression in fibroblasts. IRF7 interacts with
SMAD3 and potentiates TGFβ induced fibrosis signaling in fibroblasts. Moreover, global Irf7 knockdown
attenuates dermal fibrosis in two murine dermal fibrosis models. Lastly, our recent preliminary data suggest
fibroblast specific Irf7 knockdown might be sufficient for attenuating the bleomycin induced dermal fibrosis.
Herein, we hypothesize that IRF7 links type I IFN pathway to the fibrotic response by potentiating the TGFβ
signaling in fibroblasts which are the primary effector cells in SSc. Our primary goal is to elucidate the role of
type I IFN induced IRF7 upregulation in potentiating the TGFβ canonical pathway via IRF7 interaction
with SMAD3 in dermal fibroblasts. The following Specific Aims will be pursued:
Aim 1: Define the fibroblast specific contribution of Irf7 depletion in murine dermal fibrosis models. The
impact of fibroblast specific Irf7 depletion on dermal fibrosis in bleomycin induced and Tsk1 dermal fibrosis
models will be investigated. Aim 2: Elucidate the effects of IRF7 on SMAD3 mediated transcriptional activity
and gene expression regulation. Human fibroblast cell lines with IRF7 over-expression and deletion will be
generated and TGFβ-mediated SMAD3 transcriptional targets and gene expression regulation will be
characterized by ChIP- and RNA-sequencing in these cell lines. Aim 3: Delineate the relationship between
the peripheral blood cell interferon signature and IRF7 activation at the end-organ level in patients with
SSc. The relationship between the peripheral blood IFN signature and IRF7 expression in SSc skin tissue and
dermal fibroblast subpopulations will be characterized using bulk tissue and single cell RNA sequencing.
Cumulatively, this proposal can elucidate a key mechanism by which immune dysregulation leading to IRF7
activation potentiates the fibr...

## Key facts

- **NIH application ID:** 10477533
- **Project number:** 1R56AR078211-01
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Shervin Assassi
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $346,497
- **Award type:** 1
- **Project period:** 2021-09-22 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10477533

## Citation

> US National Institutes of Health, RePORTER application 10477533, Role of Interferon Regulatory Factor 7 in Systemic Sclerosis Pathogenesis (1R56AR078211-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10477533. Licensed CC0.

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