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Mitochondrial DNA Stress Activation of Interferon Signaling and Lupus Pathology

Award Number: R01AR069876
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY This is a new proposal aimed at characterizing a novel mitochondrial pathway of interferon (IFN) signaling we discovered and to probe its relevance to autoimmune disease pathogenesis. IFNs are essential cytokines for host defense because they provoke intrinsic antiviral states in non-immune cells and stimulate immune cells and inflammation to combat infection. They are used therapeutically for certain autoimmune diseases, cancers, and viral infection, but are also implicated in pathology when produced chronically or out of context. In our studies of a Tfam+/- mouse model of mitochondrial DNA (mtDNA) stress and normal mitochondrial responses to viral infection, we found that mtDNA release into the cytoplasm primes IFN signaling to provide enhanced antiviral immunity. This response requires binding of mtDNA to the cytoplasmic nucleic acid sensor cGAS, activation of the endoplasmic reticulum (ER)-resident protein STING, and downstream signaling to up-regulate interferon-stimulated genes (ISGs) and Type 1 IFN production. ISG expression and increased Type 1 IFN signaling contribute to the autoimmune disease systemic lupus erythematosus (SLE or lupus). Our experimental plan will systematically interrogate key remaining questions regarding this new innate immune signaling pathway, including how mtDNA is released and recognized by cGAS, are altered mitochondrial dynamics and autophagy involved, and is the pathway relevant to human diseases states where mtDNA stress has been implicated. The specific aims of the project are to 1) determine the specificity and mechanism of mtDNA sensing by cGAS, 2) decipher the role of mitochondrial dynamics (fission, fusion, autophagy) in mtDNA release and IFN signaling, including development of an innovative new mtDNA-release assay, and 3) test if mtDNA stress-mediated IFN signaling contributes to lupus pathology in mouse models and human patient cells. Significance: Completion of this project will provide significant new insight into how mtDNA stress, which is observed in many disease conditions and aging, results in innate immune pathway activation and can lead to autoimmune pathology via increased IFN production, even in the absence of a viral infection. By defining the molecular mechanisms involved, new inroads into how to augment this response to enhance antiviral immunity or prevent it under pathological circumstances (e.g. in lupus) will be made that have therapeutic potential. Furthermore, we will gain considerable new basic biology insight into mitochondrial dynamics, cytoplasmic nucleic acid recognition pathways, autophagy, and mechanisms of mtDNA damage, repair and modification.


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: 2023 ( Subtotal = $0 )
2023	2021	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	11/2/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $311,228 )
2021	2021	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	5/20/2021	NON-COMPETING CONTINUATION	$311,228
														Subtotal = $311,228

Issue Date FY: 2020 ( Subtotal = $390,184 )
2020	2020	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	5/26/2020	NON-COMPETING CONTINUATION	$390,184
														Subtotal = $390,184

Issue Date FY: 2019 ( Subtotal = $483,398 )
2019	2019	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	6/5/2019	NON-COMPETING CONTINUATION	$483,398
														Subtotal = $483,398

Issue Date FY: 2018 ( Subtotal = $517,565 )
2018	2018	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	2	6/8/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$6,278
2018	2018	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	5/30/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$517,565
2018	2017	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	6/8/2018	NEW	-$6,278
														Subtotal = $517,565

Issue Date FY: 2017 ( Subtotal = $423,563 )
2017	2017	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	2/28/2017	NEW	$423,563
														Subtotal = $423,563

Grand Total All Awards = $2,125,938

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Mitochondrial DNA Stress Activation of Interferon Signaling and Lupus Pathology

Award Number: R01AR069876

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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