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Long-term systemic consequences of type 2 skin inflammation on epithelial stem cells

Award Number: F31AR083275
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: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Long-term systemic consequences of type 2 skin inflammation on epithelial stem cells - Project Summary/Abstract Modernization has been accompanied by a marked rise in disorders of allergic inflammation. These diseases are frequently borne by epithelial barrier tissues such as the skin, lung, and gut, which provide essential protection against the inflammatory stresses of the outside world. An emerging hallmark of barrier inflammation is the ability of these tissues to durably adapt to prior experiences, enhancing future responses against a broad range of stressors. The Fuchs Lab and others have revealed that long-lived epithelial stem cells (EpSCs), which replenish and repair their tissues throughout life, are key proprietors of these barrier adaptations in the context of type 17 inflammation, generally associated with extracellular pathogen responses. Conversely, how EpSCs adapt to allergic “type 2” inflammatory exposures remains a poorly understood and urgent unmet health need. To address this critical problem, I seek to use the prevalent epithelial alarmin thymic stromal lymphopoietin (TSLP) as a driver to uncover how type 2 skin inflammation impacts the long-term functional responsiveness and epigenetic state of EpSCs. My preliminary work reveals that transient TSLP-driven type 2 skin inflammation endows resident EpSCs with long-term increased stemness in vitro, and that inflammation- experienced skin retains a concurrently heightened ability to heal wounds in vivo. Surprisingly, I discovered that this lasting hyperresponsiveness extends beyond localized sites of inflammation, as even distal EpSCs and skin maintain comparably enhanced stemness and wound repair upon resolution, despite having never seen pathologically evident inflammation. With these data in hand, I will define the specific cell-intrinsic mechanisms that distinguish TSLP-driven inflammatory memory in both local and systemic contexts, and will interrogate the niche signaling that acts on EpSCs to establish cellular and tissue-level hyperresponsiveness in each. Lastly, given that my findings thus far could help explain the puzzling frequent interlinking of atopic inflammation in the skin and airway, I will determine whether TSLP-driven skin inflammation may have parallel cross-tissue effects, and alter the long-term functionality and epigenetic state of airway EpSCs. If successful, my findings will reveal important new insights into how allergic inflammation can shape long-term, organism-wide fitness beyond antigen-specific immune sensitization and memory, and add a molecular explanation for long-standing human pathologies that could advance treatment strategies.


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 = $50,114 )
2026	2026	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	4/27/2026	NON-COMPETING CONTINUATION	$50,114
														Subtotal = $50,114

Issue Date FY: 2025 ( Subtotal = $48,974 )
2025	2025	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	4/25/2025	NON-COMPETING CONTINUATION	$48,974
														Subtotal = $48,974

Issue Date FY: 2024 ( Subtotal = $48,974 )
2024	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/11/2024	NEW	$47,694
2024	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	3/11/2024	NEW	$0
2024	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	1	6/6/2024	NEW	$1,280
														Subtotal = $48,974

Grand Total All Awards = $148,062

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Long-term systemic consequences of type 2 skin inflammation on epithelial stem cells

Award Number: F31AR083275

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: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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