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Targeting the ACOD1 immunometabolic pathway of lung myeloid cells to reduce environmental exposure-induced lung disease

Award Number: F30ES036063
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/15/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Targeting the ACOD1 immunometabolic pathway of lung myeloid cells to reduce environmental exposure-induced lung disease - PROJECT SUMMARY Environmental lung diseases are preventable disorders caused or made worse by adverse, inhaled exposures to inflammation-inducing aerosolized agents such as endotoxin (lipopolysaccharide/LPS) and microbial component-enriched organic dust. Every situation along the exposure continuum from long-term, low-level exposure to one-time, high-dose exposure can cause lung injury and subsequent disease. Anthropogenic climate change and associated industrial and agricultural intensification synergistically elevate worker and non-worker risk of adverse respiratory health outcomes. Environmental inhaled exposures can cause significant lung and airway inflammatory diseases including asthma, chronic bronchitis, pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD). Despite advances in understanding the key inflammatory signaling pathways involved in initiating the lung inflammatory response, there remains a paucity of knowledge and efficacious therapeutic options to hasten recovery and halt progression towards a chronic disease state. Our recent studies strikingly demonstrate environmental exposure-induced recruitment and activation of distinct lung monocyte- macrophage subpopulations involved in disease pathogenesis. Additionally, our bulk RNA sequencing, single cell (sc) RNA sequencing, and monocyte/macrophage subpopulation-specific transcriptomic analyses of lung homogenate harvested from mice given inhaled environmental exposures robustly implicate the aconitate decarboxylase 1 (ACOD1)-itaconate immunometabolic pathway as a potential central regulator. The proposed studies herein will be the first to investigate environmental exposure-induced lung disease through an immunometabolic lens. To this end, I hypothesize that the ACOD1-itaconate axis operates as a critical, negative regulator of lung monocyte/macrophage inflammatory processes in environmental exposure-induced lung injury and inflammation. In Specific Aim 1, I will determine the functional effect of ACOD1-itaconate pathway induction and modulation on human monocyte-derived macrophage differentiation and effector responses amidst environmental inflammatory exposures. In Specific Aim 2, the role of the ACOD1 signaling pathway in mediating lung inflammatory, resolving, and functional processes will be assessed in ACOD1 deficient mice exposed to inhaled, environmental inflammatory agents. Additionally, I will determine the therapeutic potential of lung- targeted, exogenous itaconate administration in hastening recovery following inhaled environmental exposure. The results of these studies will have an important positive impact by establishing the pre-clinical groundwork for understanding the ACOD1-itaconate axis in the context of environmental exposure-induced lung disease. Completion of these aims will optimally inform the development of novel therapies capable of preventing irreversible lung disease post-environmental exposure.


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 = $38,291 )
2025	2025	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Environmental Health	001	2	6/13/2025	NON-COMPETING CONTINUATION	$564
2025	2025	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Environmental Health	000	2	12/19/2024	NON-COMPETING CONTINUATION	$37,727
														Subtotal = $38,291

Issue Date FY: 2024 ( Subtotal = $37,727 )
2024	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Environmental Health	000	1	1/8/2024	NEW	$36,447
2024	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Environmental Health	002	1	7/19/2024	NEW	$1,280
2024	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Environmental Health	001	1	1/8/2024	NEW	$0
														Subtotal = $37,727

Grand Total All Awards = $76,018

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Targeting the ACOD1 immunometabolic pathway of lung myeloid cells to reduce environmental exposure-induced lung disease

Award Number: F30ES036063

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/15/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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