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Your Environment. Your Health.


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Principal Investigator: Holian, Andrij
Institute Receiving Award University Of Montana
Location Missoula, MT
Grant Number R21ES030978
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 18 Sep 2020 to 31 Aug 2023
DESCRIPTION (provided by applicant): Abstract Adverse outcomes following the inhalation of engineered nanomaterials, such as multi-walled carbon nanotubes (MWCNTs), have been identified in occupational settings. Unfortunately, long-term consequences and sensitive populations remain undefined. Chronic respiratory diseases often demonstrate sex-biases in disease prevalence. For example, asthma occurs more often and with increased severity in adult women compared to men. Our preliminary studies indicate that the outcomes of MWCNT exposure follow this trend: there is increased lung inflammation and injury in females compared to males. Therefore, it is logical and necessary to investigate the biological factors that may contribute to these sex-differences. There is experimental and clinical evidence that sex-steroid hormones influence the development of lung disease. A likely target of hormone signaling is alveolar macrophages (AMs), the primary resident immune cell within the lungs. The phenotype and function of AMs is an important factor in promoting specific immune responses to inhaled materials, and may contribute to inadvertent immune-mediated lung injury. This project will investigate the role of hormone signaling on AM phenotype and how this contributes to impaired lung function after exposure to MWCNTs. Current literature suggests that estrogen receptor a (ERa) signaling promotes an exaggerated M2a macrophage phenotype. The M2a phenotype promotes antibody production by B cells and is therefore associated with allergy and asthma; MWCNTs have also been shown to induce an M2a phenotype in AMs. Amplification of M2a phenotype polarization can lead to increased production of signaling molecules that cause inappropriate immune cell recruitment and inflammation, which eventually results in increased lung injury and decreased function. These data, combined with our preliminary results, provides a potential hormone-dependent mechanism for the increased susceptibility of women to allergens and nanomaterials. This project will address the hypothesis that estrogen signaling through ERa promotes an exaggerated M2a phenotype in female AMs, which contributes to the increased occurrence and severity of particle-induced respiratory diseases in women.
Science Code(s)/Area of Science(s) Primary: 78 - Nanotoxicology
Secondary: 03 - Carcinogenesis/Cell Transformation
Publications See publications associated with this Grant.
Program Officer Lingamanaidu Ravichandran
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