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Interferon Regulatory Factor 7 Links Interferon Pathway Activation to the Exaggerates Fibrotic Response in Systemic Sclerosis

Award Number: R01AR081280
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Interferon Regulatory Factor 7 Links Interferon Pathway Activation to the Exaggerates Fibrotic Response in Systemic Sclerosis - 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, as well as a prominent regulator of SSc fibroblasts. 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 functional 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. Aim 3: Delineate the relationship between the peripheral blood cell interferon signature and IRF7 upregulation 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 and single cell RNA sequencing. Cumulatively, this proposal can elucidate a key mechanism by which immune dysregulation leading to IRF7 activation potentiates the fibrotic response in SSc. Ultimately, this can open the door to identification of more targeted and effective treatment options for this potentially devastating disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $319,352 )
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	4/29/2025	NON-COMPETING CONTINUATION	$319,352
														Subtotal = $319,352

Issue Date FY: 2024 ( Subtotal = $321,060 )
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	5/3/2024	NON-COMPETING CONTINUATION	$297,890
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	6/4/2024	NON-COMPETING CONTINUATION	$23,170
														Subtotal = $321,060

Issue Date FY: 2023 ( Subtotal = $224,865 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	5/1/2023	NEW	$224,865
														Subtotal = $224,865

Grand Total All Awards = $865,277

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Interferon Regulatory Factor 7 Links Interferon Pathway Activation to the Exaggerates Fibrotic Response in Systemic Sclerosis

Award Number: R01AR081280

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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