Targeting the ACOD1 immunometabolic pathway of lung myeloid cells to reduce environmental exposure-induced lung disease
Ended Project Grant Awarded Last action
- Award ID
- F30ES036063
- Recipient
-
Board Of Regents Of The University Of Nebraska UEI G15AG3BLLMH4 Part of Board Of Regents Of University Of Nebraska
- Awarding agency
-
National Institute of Environmental Health Sciences
National Institutes of Health, Department of Health and Human Services
- Obligated
- $262,093
Award facts
- Assistance listing
- 93.113 Environmental Health
- Completion date
- Place of performance
- Nebraska, USA
Award details come from USAspending.gov.
Description
- Abstract
- 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.
Transactions
| Action | Obligated | Date |
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| Amendment | $564 | |
| Amendment | $37,727 | |
| Amendment | $37,727 | |
| Amendment | $1,280 | |
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| Amendment | $36,447 | |
| Amendment | $0 | |
| Amendment | $36,447 | |
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| Amendment | $36,447 | |
| Amendment | $36,447 | |
| Amendment | $0 | |
| Amendment | $36,447 | |
| Original award | $0 |
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Quick answers
Who received award F30ES036063?
F30ES036063 was awarded to Board Of Regents Of The University Of Nebraska by National Institute of Environmental Health Sciences (National Institutes of Health) on June 30, 2024.
How much is award F30ES036063 worth?
$262,093 has been obligated on F30ES036063.
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