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Glutaredoxin-Mediated Redox Processes Control Aberrant Plasticity of Airway Basal Stem Cells and Crosstalk with Mesenchymal Cells

Award Number: F31HL186664
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/15/2026
PERIOD OF PERFORMANCE END DATE: 12/14/2027

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Glutaredoxin-Mediated Redox Processes Control Aberrant Plasticity of Airway Basal Stem Cells and Crosstalk with Mesenchymal Cells - PROJECT SUMMARY Idiopathic pulmonary fibrosis (IPF) is a devastating disease that affects nearly 40,000 people each year and has a median survival of 3-5 years post-diagnosis. Current therapies to treat IPF aim to improve disease symptoms but have not been effective at increasing life span. An enhanced oxidative environment has long been characterized as an important feature in the pathophysiology of chronic lung diseases, yet clinical trials using antioxidants have yielded no therapeutic effect on lung function or survival for patients with IPF. We believe these approaches have failed due to an incomplete understanding of how redox processes contribute to the progression of IPF. Our laboratory has identified that protein S-glutathionylation (PSSG), a redox-based modification of reactive protein cysteines, plays a critical role in the progression of lung fibrosis whereby the enzyme responsible for reversing this modification, glutaredoxin-1 (GLRX), is inactivated. The intriguing observations around the PSSG-GLRX axis have formed the foundation of the research directions proposed herein where we aim to define the cell- and location-specific impact of GLRX inactivation and redox imbalance during fibrogenesis. Recent studies have highlighted the significance of dysregulated basal cell fate and function in the progression of lung fibrosis. Keratin 5-expressing (KRT5) basal cells are resident progenitor cells of the airway that accumulate at sites of lung injury and establish an injury-induced niche with residential fibroblasts that promote fibrogenesis. Oxidative signals have been shown to regulate basal cell function under homeostatic conditions, yet it is unclear whether its dysregulation may contribute to aberrant basal cell activity seen during fibrosis development. We hypothesize that PSSG serves as both a mediator of basal cell function and profibrotic cue within the injury-induced niche to promote fibrosis. To address this hypothesis, we will use Krt5 lineage- labeled conditional knockout (CKO) mice to ablate Glrx in basal cells and assess the functional significance of GLRX in dictating basal cell behavior and driving dysplastic lung repair. Basal cell-mesenchymal crosstalk under GLRX-mediated redox control will be examined as an extension of basal cell plasticity. This research proposal incorporates an integrative approach combining organoid cultures, in vivo mouse models, and multi-omics profiling, including both transcriptomic and proteomic analyses, to uncover a previously unrecognized molecular mechanism that could underlie basal cell pathogenicity. The rigorous research environment fostered by Dr. Janssen-Heininger and The University of Vermont Larner College of Medicine will ensure the research training to be comprehensive and of exceptional quality, supported through access to core facilities and both an immediate and extended scientific community. Collectively, the proposed studies will yield key mechanistic insights into the redox-based pathways that mediate fibrosis development to guide translational approaches aimed to promote proper lung repair.


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: 2026 ( Subtotal = $37,446 )
2026	2026	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	000	1	6/16/2026	NEW	$37,446
														Subtotal = $37,446

Grand Total All Awards = $37,446

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Glutaredoxin-Mediated Redox Processes Control Aberrant Plasticity of Airway Basal Stem Cells and Crosstalk with Mesenchymal Cells

Award Number: F31HL186664

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/15/2026

PERIOD OF PERFORMANCE END DATE: 12/14/2027

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