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Mechanisms of STING-associated autoinflammation

Award Number: R01AI143982
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: 03/01/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Mechanisms of STING-associated autoinflammation - Project Abstract The goal of this proposal is to define novel functions of STING in autoinflammation, cytokine secretion, and immune dysregulation mediated by macrophages, innate lymphoid cells, and radioresistant cells. This work builds on our prior discoveries using our model of STING-associated autoinflammation. The proposed studies utilize several newly generated, already-validated model systems that will allow us to define cell type-specific functions of STING in autoinflammatory disease pathogenesis. STING gain-of-function mutations cause STING-associated vasculopathy with onset in infancy (SAVI), an autoinflammatory disease characterized by T cell cytopenia, interstitial lung disease, Raynaud’s, skin lesions, vasculopathy, and up-regulation of interferon (IFN)-stimulated genes. We previously generated a mouse model of SAVI and discovered that the disease is mediated by type II IFN (IFN-γ) rather than type I or type III IFN. This discovery was unexpected since type I IFN had been predicted to mediate disease. Additionally, we found that innate lymphoid cell functions are altered in STING gain-of-function mice, and that macrophage activation phenotypes and cytokine secretion are perturbed by constitutive STING signaling. We have previously generated and published our floxed-STOP STING mutant mice, which permit cell type-specific expression of STING. However, we have not yet studied cell type-specific functions of the type II IFN receptor and STING in myeloid cells, innate lymphoid cells, and radioresistant cells in our model of STING-induced autoinflammation. Therefore, we will define functions of the type II IFN receptor (Aim 1) and the effects of cell type-specific expression of STING (Aim 2) in SAVI mice. In unbiased, whole-genome CRISPR screening studies, we were led to the discovery that both WT STING and STING gain-of-function can non-transcriptionally regulate pro-inflammatory cytokine secretion by altering the post-Golgi endosomal pathways, and that this occurs without impacting secretion of other proteins. This function of STING requires the protein ArfGAP2. Additionally, we found that ArfGAP2 deletion has no appreciable effect on Golgi structure or on the transit of proteins from the ER to the Golgi when STING is inactive. However, when STING is activated, cytokine trafficking and secretion is greatly diminished in the absence of ArfGAP2, and this effect is non-transcriptional. We generated Arfgap2f/f mice crossed to transgenic Cre animals, and we found that ArfGAP2 is deleted efficiently without impacting survival of target cells. In Aim 3, we will define the immunological and physiological functions of ArfGAP2 in STING-mediated cytokine secretion and autoinflammation (Aim 3).


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 = $620,851 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	8	12/20/2024	NON-COMPETING CONTINUATION	$620,851
2025	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	002	7	2/14/2025	COMPETING CONTINUATION	$342,188
2025	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	6	2/14/2025	NON-COMPETING CONTINUATION	-$342,188
														Subtotal = $620,851

Issue Date FY: 2024 ( Subtotal = $640,052 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	002	7	9/4/2024	COMPETING CONTINUATION	$64,006
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	7	3/15/2024	COMPETING CONTINUATION	$576,046
2024	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	6	3/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $640,052

Issue Date FY: 2023 ( Subtotal = $554,202 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	6	2/2/2023	NON-COMPETING CONTINUATION	$554,379
2023	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	000	3	11/21/2022	NON-COMPETING CONTINUATION	-$177
														Subtotal = $554,202

Issue Date FY: 2022 ( Subtotal = $578,885 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	002	5	2/14/2022	NON-COMPETING CONTINUATION	$563,885
2022	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	004	4	5/24/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$62,874
2022	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	003	3	5/24/2022	NON-COMPETING CONTINUATION	-$62,874
2022	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	3	1/10/2022	NON-COMPETING CONTINUATION	-$472,539
2022	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	4	1/10/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$487,539
														Subtotal = $578,885

Issue Date FY: 2021 ( Subtotal = $554,372 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	3	2/3/2021	NON-COMPETING CONTINUATION	$554,372
														Subtotal = $554,372

Issue Date FY: 2020 ( Subtotal = $560,009 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	2	3/2/2020	NON-COMPETING CONTINUATION	$560,009
														Subtotal = $560,009

Issue Date FY: 2019 ( Subtotal = $466,883 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	1	12/26/2018	NEW	$466,883
														Subtotal = $466,883

Grand Total All Awards = $3,975,254

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Mechanisms of STING-associated autoinflammation

Award Number: R01AI143982

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: 03/01/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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