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Role of Splenic Pro-Resolving Mediators During Exposure to Particulate Air Pollution

Award Number: R01ES034389
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2023
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Role of Splenic Pro-Resolving Mediators During Exposure to Particulate Air Pollution - Exposure to ambient particulate matter (PM) is a risk factor for cardiovascular disease. Although the mechanisms by which PM induces pervasive multi-organ injury are still under investigation, evidence strongly implicates chronic inflammation as a primary driver of pathology. Whether exposure to fine PM (PM2.5) specifically impairs the endogenous pathways that promote the resolution of inflammation is not known. Therefore, the long-term goal of this project is to determine how exposure to PM impacts the resolution of inflammation and whether this contributes to PM exposure-exacerbated atherosclerosis. In work in progress, we discovered that in mice exposed to concentrated PM (PM2.5) for 30 days circulating erythrocytes expressed markers of premature aging and oxidative damage. In the spleens of these mice there was an expansion of the population of cells responsible for erythrocyte disposal, red pulp macrophages, while pathways related to erythrocyte turnover, heme metabolism, and iron cycling were upregulated. Additionally, we found that several factors related to hematopoiesis were induced in the tissue. These alterations were accompanied by a marked decrease in the abundance of specialized lipid mediators that promote resolution (SPMs) and their receptors. The changes in spleen are particularly critical because the spleen plays a central role in regulating immune response dynamics. It houses an important and distinct reservoir of monocytes, which can be rapidly mobilized and deployed in response to various insults. In addition to coordinating immune function, the spleen acts as a filter to remove senescent and damaged erythrocytes. Though patients survive following splenectomy, they are more likely to contract serious and life-threatening infections and have heightened risk of developing hematological malignancies and coronary artery disease among other disorders. Our preliminary studies suggest that exposure to PM2.5 may disrupt splenic homeostasis with targeted impacts on red pulp macrophages. As macrophages are the critical facilitators of erythrophagocytosis, maintenance of the splenic hematopoietic niche, and SPM actions, our central hypothesis is that PM2.5 exposure increases splenic macrophage erythrophagocytosis, which suppresses SPM production and permits local myelopoiesis, thereby enhancing monocyte egress and exacerbating vascular inflammation. To test this hypothesis, we will examine the effects of PM2.5 exposure on splenic macrophages, determine the impact of PM2.5 exposure on the splenic hematopoietic niche and delineate the contribution of splenic myelopoiesis to PM2.5-exacerbated atherosclerosis. This project will elucidate the effects of PM on the resolution of inflammation and will provide a new mechanism by which exposure to PM establishes a state of chronic, non-resolving inflammation that affects multiple organs and processes.


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: 2026 ( Subtotal = $564,543 )
2026	2026	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Environmental Health	000	4	3/5/2026	NON-COMPETING CONTINUATION	$564,543
														Subtotal = $564,543

Issue Date FY: 2025 ( Subtotal = $568,103 )
2025	2025	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Environmental Health	000	3	3/7/2025	NON-COMPETING CONTINUATION	$568,103
														Subtotal = $568,103

Issue Date FY: 2024 ( Subtotal = $569,826 )
2024	2024	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Environmental Health	000	2	2/14/2024	NON-COMPETING CONTINUATION	$569,826
														Subtotal = $569,826

Issue Date FY: 2023 ( Subtotal = $566,366 )
2023	2023	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Environmental Health	000	1	4/24/2023	NEW	$566,366
														Subtotal = $566,366

Grand Total All Awards = $2,268,838

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Role of Splenic Pro-Resolving Mediators During Exposure to Particulate Air Pollution

Award Number: R01ES034389

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2023

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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