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Dissecting the Role of Arachidonic Acid Metabolic Pathways Involved in Resolution Versus Progression of PM-Induced Cardiometabolic Toxicity

Award Number: R01ES033703
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT Epidemiological and experimental data have shown that chronic exposure to ambient particulate matter (PM) leads to exacerbation of atherosclerosis, and increased cardiovascular morbidity and mortality. We have shown that mouse exposures to diesel exhaust and ultrafine particles (PM< 0.18 µm) lead to increased lipid peroxidation in the lungs and systemic tissues, accompanied by effects on plasma lipoproteins, disturbances in lipid metabolism, liver steatosis, and atherosclerosis, all components of the so-called cardiometabolic syndrome. PM- induction of these disorders is thought to involve chronic and persistent activation of inflammatory pathways. However, while chronic exposure to PM < 2.5 µm (PM2.5) has been reported to result in steatohepatitis, we have shown that chronic exposure to diesel exhaust also leads to triglyceride accumulation in the liver (steatosis) but without the inflammatory component, suggesting that PM with different compositions could have different abilities to activate inflammatory pathways after chronic exposures. This project has been designed to dissect molecular pathways involved in the development and progression versus inhibition or resolution of inflammation. Our central hypothesis is that PM exposure promotes cardiometabolic toxicity via prooxidant and proinflammatory effects that lead to wide dysregulation of arachidonic acid metabolic pathways, with activation of 5-lipoxygenase, overpowering the counteracting actions of homeostatic protective responses when that activation is persistent. We will test this hypothesis via three specific aims: 1) Determine molecular pathways involved in the inhibition of steatohepatitis after exposure to diesel exhaust. 2) Dissect molecular pathways and toxic constituents involved in the development and progression of steatohepatitis and atherosclerosis after exposure to ultrafine particles. 3) Determine whether PM-induced chronic inflammation is mediated by the persistent activation of the 5-lipoxygenase (5-LO) pathway, and explore the therapeutic potential of blocking this pathway to mitigate the cardiometabolic toxicity and resolve inflammation induced by PM. In aims 1 and 2, LDL-R KO mice will be exposed to whole diesel exhaust or ultrafine concentrated ambient particles, respectively, to evaluate the effect of different PMs on the development of fatty liver disease and atherosclerosis in experimental protocols of continuous or intermittent exposures to PM. Intervening molecular pathways will be analyzed in various tissues (lungs, blood, liver, aorta), especially those involving arachidonic acid metabolism and antioxidant homeostatic responses. Data will be integrated with inflammatory endpoints obtained in various tissues, alveolar and systemic macrophages. Comparison among contrasting effects observed in both aims will enable identification of critical pathways responsible for development versus resolution of chronic inflammation. In aim 3, LDL-R KO mice deficient in 5-LO or treated with pharmacological inhibitors of the 5-LO pathway will be tested to evaluate the role of 5-LO activation in mediating PM-induced inflammation. This project will help in better understanding of PM-induced toxicity with prophylactic or therapeutic implications.


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 = $513,320 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Environmental Health	000	3	12/8/2023	NON-COMPETING CONTINUATION	$513,320
														Subtotal = $513,320

Issue Date FY: 2023 ( Subtotal = $883,607 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Environmental Health	001	2	5/17/2023	SUPPLEMENT FOR EXPANSION	$362,050
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Environmental Health	000	2	11/10/2022	NON-COMPETING CONTINUATION	$521,557
														Subtotal = $883,607

Issue Date FY: 2022 ( Subtotal = $543,455 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Environmental Health	000	1	2/11/2022	NEW	$543,455
														Subtotal = $543,455

Grand Total All Awards = $1,940,382

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Dissecting the Role of Arachidonic Acid Metabolic Pathways Involved in Resolution Versus Progression of PM-Induced Cardiometabolic Toxicity

Award Number: R01ES033703

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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