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Elucidating the Cellular and Molecular Basis of Fibroinflammation

Award Number: R56AR087127
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Elucidating the Cellular and Molecular Basis of Fibroinflammation - Project Summary Fibrosing diseases of the skin are highly morbid conditions with a large unmet medical need. These diseases are strongly associated with tissue inflammation (termed ‘fibroinflammation’). It is thought that both the quality and quantity of these inflammatory reactions play a major role in dictating whether fibrosis will occur and how severe it will be. The cellular and molecular pathways that drive fibroinflammation remain to be fully elucidated. We have discovered that CD8+ T cells play a major role in driving fibroinflammation. In addition, we have identified a novel population of skin fibroblasts that are highly responsive to inflammatory cytokines and rapidly expand in this context. The central focus of this grant application is to elucidate the cellular and molecular mechanisms by which CD8+ T cells and the newly discovered Pi16 expressing fibroblasts (PiFs) contribute to fibroinflammation. We hypothesize that when there is a reduction in tissue immune regulation, CD8+ T cells kill adipocytes, either directly through adipocyte-specific antigen recognition or indirectly through secretion of cytokines that adipocytes are exquisitely sensitive to. We further hypothesize that in this setting, both type 1 and type 2 immune responses activate PIFs and drive them towards a pro-inflammatory and pro-fibrotic state. The combination of adipocyte death and activation of PIFs work in concert to create a unique microenvironment that facilitates pro-fibrotic inflammation. These hypotheses will be tested using a novel murine model of skin fibroinflammation resulting from a transient reduction in regulatory T cells (Tregs) early in life. In addition, we have generated a new transgenic mouse strain to interrogate the fundamental biology of PiFs, with a focus on discerning the inflammatory pathways responsible for activating these cells. We employ innovative and cutting-edge methodology to test our hypotheses, including skin specific genetic manipulation of immune cells and an adeno-associated virus (AAV) system to selectively genetically modify PiFs. Through these lines of investigation, we will achieve a better understanding of the pathways that drive pro-fibrotic inflammation in attempts to inform novel treatment strategies targeting fibrosing diseases at the fibroinflammatory stage, possibly halting progression to fulminant organ fibrosis.


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 = $300,000 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/9/2026	NEW	$300,000
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	9/11/2026	NEW	$0
														Subtotal = $300,000

Grand Total All Awards = $300,000

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Elucidating the Cellular and Molecular Basis of Fibroinflammation

Award Number: R56AR087127

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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