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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=R00ES032473&format=word)
| Principal Investigator: Smith, Ley C | |
|---|---|
| Institute Receiving Award | University Of Connecticut Storrs |
| Location | Storrs Mansfield, CT |
| Grant Number | R00ES032473 |
| Funding Organization | National Institute of Environmental Health Sciences |
| Award Funding Period | 01 May 2023 to 30 Apr 2026 |
| DESCRIPTION (provided by applicant): | PROJECT SUMMARY (See instructions): Macrophages contribute to ozone toxicity by regulating both the initiation and resolution of lung inflammation; these processes are mediated by distinct macrophage subpopulations broadly classified as proinflammatory/cytotoxic (M1) and anti-inflammatory/wound repair (M2) macrophages. M1 and M2 macrophage activation is controlled, in part, by intracellular metabolism; thus, while high glycolytic capacity is associated with M1 activity, increases in fatty acid oxidation and mitochondrial oxidative phosphorylation are required for M2 macrophage activation. New data suggest that ozone toxicity is due to impaired M2 activation and a failure to resolve inflammation, however, mechanisms are not known. A preliminary RNAseq analysis of lung macrophages collected after ozone exposure revealed significant enrichment of the estrogen receptor signaling pathway among differentially expressed genes. This was associated with an increase in glycolytic metabolism and down-regulation of PPARγ expression, a transcription factor known to promote M2 phenotype and resolution of inflammation by shifting intracellular metabolism to fatty acid oxidation. Estrogen has been shown to regulate PPARγ expression by activating estrogen receptor alpha (ESR1) located at the cell membrane, and to promote macrophage anti-inflammatory activity by shifting metabolism to fatty acid oxidation; we speculate that this pathway is important in macrophage responses to ozone. We hypothesize that ozone interferes with extra-nuclear ESR1 signaling in macrophages and downstream activation of PPARγ; this leads to impaired fatty acid oxidation and M2 macrophage activation resulting in aberrant resolution of inflammation and increased tissue injury. Two aims are proposed to test this hypothesis. In the first aim, I will analyze the role for ESR1 signaling in macrophage immunometabolism and phenotypic activation. Aim 2 will focus on 1) elucidation of mechanisms by which ozone interferes with extra-nuclear ESR1 signaling, 2) the role of extra-nuclear ESR1 in macrophage bioenergetics and phenotype in response to ozone and how this influences lung injury, and 3) developing strategies to mitigate ozone-induced lung injury by rescuing extra-nuclear ESR1 signaling. Results of these studies will provide novel data on general mechanisms underlying macrophage responses to inhaled ozone and mechanistic evidence supporting sex-based differences in pulmonary responses. Findings that ESR1 is critical in these pathways will highlight estrogen signaling as a key driver of sexual dimorphism in lung disease and indicate that individualized exposure limits and therapeutic strategies may be required to prevent disease and to target distinct pathways driving toxicity in men and women. I will leverage my training in macrophage biology, ESR1 signaling, bioinformatics, and intracellular metabolism acquired during the K99 award period to develop an independent research program at my new institution focused on elucidating estrogen receptor signaling networks regulating inflammation in environmentally induced lung disease. |
| Science Code(s)/Area of Science(s) |
Primary: 69 - Respiratory Secondary: 03 - Carcinogenesis/Cell Transformation |
| Publications | See publications associated with this Grant. |
| Program Officer | Srikanth Nadadur |