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EGFR C797 is an oxidative sensor that regulates response to oxidative stress

Award Number: F31AR088289
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 11/16/2026
PERIOD OF PERFORMANCE END DATE: 11/15/2028

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EGFR C797 is an oxidative sensor that regulates response to oxidative stress - SUMMARY Scleroderma/systemic sclerosis (SSc) is a lethal autoimmune disease that causes fibrosis of the skin and internal organs. Oxidative stress is a fundamental feature of SSc, but its role in pathogenesis is poorly understood. Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that drives fibrosis in SSc skin and lung and other fibrotic diseases like idiopathic pulmonary fibrosis and chronic kidney disease. EGFR contains an exposed cysteine (C797) susceptible to oxidation that has been reported to function as an oxidative sensor. The importance of C797 is highlighted by its high structural conservation among 10 kinases including two other ERBB family members. Functionally, oxidation of EGFR C797 via sulfenylation has been reported to increase EGFR kinase activity and regulate extracellular matrix (ECM) gene expression during wound healing. However, the mechanism linking EGFR C797 oxidation and its regulation of reactive oxygen species (ROS) response in the context of fibrosis remains unclear. In preliminary studies, we found that EGFR is sulfenylated in primary fibroblasts and its activation drives ROS production and scavenging. To understand the importance of EGFR C797 on the organism level, we generated mice with the homologous EGFR C799 mutated to glycine rendering it resistant to modification (EgfrC799G). Preliminary data in EgfrC799G mice demonstrated features of dysregulated ROS, including decreased skin laxity and delayed wound healing with associated increased expression of ROS producers and decreased ROS scavengers. The goal of this proposal is to mechanistically understand how EGFR oxidative sensing regulates ROS and consequently severity of skin fibrosis. We will evaluate this concept in two aims. In Aim 1, I will determine how EGFR signaling regulates ROS production and scavenging in healthy and SSc skin fibroblasts. I will assess EGFR activation in healthy compared to SSc fibroblasts for cellular ROS levels relative to EGFR sulfenylation and kinase activity. I will evaluate the cellular sources of ROS including NADPH oxidases and mitochondria function. Then, using EgfrC799G compared to wild type fibroblasts, I will measure EGFR sulfenylation, NRF2 activity and cellular ROS levels. In Aim 2, we will investigate the impact of EGFR oxidative sensing to regulate skin fibrosis. EgfrC799G will be compared to wild type mice for severity of skin fibrosis using the bleomycin mouse model. NRF2 activity will be rescued by treatment with sulforaphane and its effects on ROS-related outcomes and NRF2 nuclear trafficking. These aims will address a key signaling mechanism by which EGFR oxidative sensing regulates cellular functions including ROS balance and fibrosis, which will provide critical insight into the pathogenesis of SSc and other fibrotic diseases.


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: 2027 ( Subtotal = $0 )
2027	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	10/6/2026	NEW	$0
2027	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	10/6/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2026 ( Subtotal = $50,114 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/17/2026	NEW	$50,114
														Subtotal = $50,114

Grand Total All Awards = $50,114

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EGFR C797 is an oxidative sensor that regulates response to oxidative stress

Award Number: F31AR088289

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 11/16/2026

PERIOD OF PERFORMANCE END DATE: 11/15/2028

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