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Synergistic effects of silica exposure, virus infection and genetic predisposition in systemic autoimmunity

Award Number: R01ES031082
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, is characterized by immune system hyperactivation, autoantibody production, and multiorgan inflammation. Although genetic predisposition is critical for disease expression, the low concordance rate in monozygotic twins (<40%) suggests the essential contribution of additional factors, mostly provided through environmental exposures. Indeed, significant epidemiological evidence has linked SLE and other systemic autoimmune disease to crystalline silica exposure but also to certain viral infections. Considering the critical role of innate immune activation in systemic autoimmunity, we hypothesized that silica inhalation, virus infection, and genetic predisposing factors synergize by activating distinct innate immunostimulatory pathways, that together lead to more efficient break of tolerance, earlier disease onset, and more severe autoimmune manifestations. In support of this hypothesis, we provide preliminary evidence that silica and virus exposures more effectively induce autoimmune manifestations in mouse models of lupus when given in combination than when given individually. Here we will use this experimental system to define the mechanistic basis of the interplay between virus infection and silica, including the temporal requirements of silica exposure and virus infection, the contribution of innate inflammatory pathways differentially induced by silica and virus, and roles of these factors in breaking immunological tolerance.


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: 2024 ( Subtotal = $421,872 )
2024	2024	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT STE 200	SAN DIEGO	CA	92121	SAN DIEGO	USA	Environmental Health	000	5	5/3/2024	NON-COMPETING CONTINUATION	$421,872
														Subtotal = $421,872

Issue Date FY: 2023 ( Subtotal = $415,655 )
2023	2023	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Environmental Health	000	4	4/25/2023	NON-COMPETING CONTINUATION	$415,655
														Subtotal = $415,655

Issue Date FY: 2022 ( Subtotal = $422,311 )
2022	2022	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Environmental Health	000	3	4/29/2022	NON-COMPETING CONTINUATION	$422,311
														Subtotal = $422,311

Issue Date FY: 2021 ( Subtotal = $855,965 )
2021	2021	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	10865 ROAD TO THE CURE STE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Environmental Health	004	2	8/26/2021	SUPPLEMENT FOR EXPANSION	$423,965
2021	2021	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Environmental Health	003	2	8/21/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$120,280
2021	2021	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	10865 ROAD TO THE CURE STE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Environmental Health	001	2	3/28/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$432,000
2021	2020	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Environmental Health	000	1	3/27/2021	NEW	$0
2021	2020	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Environmental Health	002	1	8/21/2021	NEW	-$120,280
														Subtotal = $855,965

Issue Date FY: 2020 ( Subtotal = $399,375 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Environmental Health	000	1	6/29/2020	NEW	$399,375
														Subtotal = $399,375

Grand Total All Awards = $2,515,178

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Synergistic effects of silica exposure, virus infection and genetic predisposition in systemic autoimmunity

Award Number: R01ES031082

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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