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PD-L1 reverse signaling in liver homeostasis and disease

Award Number: R01AI186275
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2025
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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PD-L1 reverse signaling in liver homeostasis and disease - This Project Summary/Abstract was originally submitted with R01 AI186275 and is included here unchanged to satisfy submission system requirements. PROJECT SUMMARY The goal of this proposal is to identify the mechanism(s) by which programmed death ligand 1 (PD-L1) reverse or intracellular signaling acts as an immune regulator in the liver during both acute infection, chronic infection and chronic disease. Our studies have outlined a major role for PD-L1 reverse signaling in the control of dendritic cell (DC) migration, DC activation and in regulating T cell cytokine production. These findings are consistent with PD-L1 acting to mitigate type 1 interferon (IFN) signaling events. Using a murine model where just three amino acids in the cytoplasmic domain of PD-L1 are mutated to alanine, to limit reverse signaling, we find increased fibrosis in a murine model of Metabolic dysfunction-associated steatohepatitis (MASH) and decreased liver pathology in an acute systemic listeria infection model. Therefore, in this proposal we aim to better understand the different functions of PD-L1 reverse signaling (ie, DC migration vs activation) and how they contribute to T cell programming in listeria infection and MASH. We also aim to better understand which PD-L1 expressing cells in the liver contribute to effector T cell responses and liver fibrosis in the absence of PD-L1 reverse signaling using a murine model of MASH. Finally, we aim to address the importance of PD-L1 reverse signaling in the liver in the setting of acute versus chronic infection of LCMV. Together these Aims will define how a widely targeted immune regulatory molecule, PD-L1, functions in the liver through intracellular signaling events not previously recognized or appreciated.


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 = $611,537 )
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	1	11/13/2024	SUPPLEMENT FOR EXPANSION	$28,803
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	002	1	5/16/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	001	2	4/16/2025	NON-COMPETING CONTINUATION	$582,734
														Subtotal = $611,537

Issue Date FY: 2024 ( Subtotal = $582,734 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	001	1	9/3/2024	NEW	$58,272
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	1	5/30/2024	NEW	$524,462
														Subtotal = $582,734

Grand Total All Awards = $1,194,271

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PD-L1 reverse signaling in liver homeostasis and disease

Award Number: R01AI186275

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2025

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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