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Novel Approaches for Improving Inflammation Resolution Following Chronic Exposure to Air Pollutants

Award Number: R01ES033660
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Novel Approaches for Improving Inflammation Resolution Following Chronic Exposure to Air Pollutants - Abstract Inflammation is a necessary biological response to injury, infection, and environmental exposures, and a well- orchestrated physiological process, which if unchecked produces undesirable toxicity. Unresolved inflammation contributes to the development of chronic diseases exacerbated by environmental exposures. The molecular mechanisms and players of resolution of inflammation are not well understood. In this application, we will examine two novel pathways that we hypothesize to play a critical role in the resolution of inflammation. 1. We previously reported that diesel exhaust particle extracts and associated polycyclic aromatic hydrocarbons inhibit COX2-dependent eicosanoid synthesis in murine macrophages. While COX2 is commonly thought to be pro- inflammatory, Cox2 macrophage-specific knock-out (Cox2MKO) mice develop intestinal inflammation when fed a high fat diet. Macrophage COX2 thus appears to provide an inhibitory molecular check on chronic inflammation mediated by dietary and environmental exposures. In preliminary experiments, we show that loss of COX2 impaired efferocytosis in mouse primary macrophages and COX2 modulated the production of efferocytosis- dependent lipid inflammatory mediators that not only affect secondary efferocytosis but also induce a tissue repair phenotype in intestinal epithelial organoids. Under specific aim 1, based on published and recent preliminary results, we will test the hypothesis that macrophage COX2-dependent eicosanoids play a critical role in chronic inflammatory diseases exacerbated by environmental pollutants. 2. Our laboratory pioneered the development of amphipathic peptides that mimic the antioxidant and anti-inflammatory properties of apolipoprotein A-I (apoA-I). ApoA-I mimetic peptides (4F) inhibit the development of inflammatory diseases that are exacerbated by dietary and environmental exposures including atherosclerosis and intestinal inflammation. We demonstrated that 4F attenuates ambient ultrafine particle (UFP)-mediated oxidative stress, lipid metabolism, atherosclerosis and intestinal inflammation. A common mechanism of protective action of 4F in all these disease models is by tilting the net balance of lipid mediators of inflammation to an anti-inflammatory state, in the circulation and tissues. In preliminary results, we demonstrated that apoA-I mimetic peptides enhance transintestinal lipid transport (TILT) ex vivo and in vivo. Under specific aim 2, we will test the hypothesis that TILT is a key mediator of resolution of inflammation and plays an important role in the development of chronic inflammatory diseases exacerbated by environmental exposures. Successful completion of the studies proposed in this new R01 application will not only advance our understanding of the biology and molecular mechanisms underlying the effects of environmental exposures on the resolution of inflammation but also provide novel therapeutic strategies in our fight against chronic inflammatory diseases exacerbated by air pollution.


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 = $417,236 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Environmental Health	000	4	2/14/2025	NON-COMPETING CONTINUATION	$417,236
														Subtotal = $417,236

Issue Date FY: 2024 ( Subtotal = $469,879 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Environmental Health	000	3	12/21/2023	NON-COMPETING CONTINUATION	$469,879
														Subtotal = $469,879

Issue Date FY: 2023 ( Subtotal = $472,252 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Environmental Health	000	2	12/23/2022	NON-COMPETING CONTINUATION	$472,252
														Subtotal = $472,252

Issue Date FY: 2022 ( Subtotal = $488,553 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Environmental Health	000	1	3/1/2022	NEW	$459,807
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Environmental Health	001	1	4/11/2022	NEW	$28,746
														Subtotal = $488,553

Grand Total All Awards = $1,847,920

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Novel Approaches for Improving Inflammation Resolution Following Chronic Exposure to Air Pollutants

Award Number: R01ES033660

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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