A multi-disciplinary study into air pollution-associated transition metal homeostasis in the lungs.

颗粒物(PM)空气污染来源广泛，是导致健康不佳的主要风险因素。然而，我们对颗粒物中与颗粒物来源有关的不同成分对肺的影响了解较少。这对于理解为什么某些类型的PM比其他类型的PM毒性更大是很重要的。我们特别感兴趣的是PM中的金属如何推动肺部疾病的发展和恶化，如特发性肺纤维化。我们小组最近的工作表明，与运输相关的超细PM(PM的最小粒度部分)富含钒和镍，并且这种PM以及单独的钒和镍对暴露的电池产生多种影响。我们还观察到了来自不同来源的颗粒物中其他过渡金属的影响，例如地下铁路。我们现在热衷于了解PM金属如何在细胞内积累，细胞如何维持细胞内金属(金属组)的动态平衡，以及如果这一过程失败的后果。在这个多学科的项目中，我们将研究过渡金属，最初集中在钒和镍，如何在肺泡上皮细胞内差异积累，并影响，评估金属运输/结合蛋白所扮演的角色。主要目的是：1.研究金属转运蛋白和金属结合蛋白对钒和镍暴露的响应。使用最先进的质谱学技术，调查暴露在电池中的钒和镍的积累，以及对其他金属的动态平衡的影响。利用药理学和/或基因技术研究观察到的效应发生的机制及其功能障碍的后果。该项目的结果将扩大我们对细胞如何对空气中PM的不同金属成分做出反应的理解，以及来自不同来源的PM如何在推动肺部疾病中发挥重要作用。

Particulate matter (PM) air pollution, which comes from a wide range of sources, is a leading risk factor for ill health. However, our understanding of effects on the lung of different components of PM, which relate to PM source, is poor. This is important in understanding why some types of PM may be more toxic than others. We are especially interested in how metals in PM may drive development and exacerbation of lung diseases such as idiopathic pulmonary fibrosis. Recent work in our group has shown that ultrafine PM (the smallest size fraction of PM) associated with shipping is enriched in vanadium and nickel, and that this PM, as well as vanadium and nickel alone, exerts multiple effects on exposed cells. We have also observed effects associated with other transition metals in particles from different sources, such as underground railways. We are now keen to understand how PM metals accumulate within cells, how cells maintain homeostasis of intracellular metals (the metallome), and the consequences if this fails.In this multidisciplinary project, we will study how transition metals, focusing initially on vanadium and nickel, may differentially accumulate within, and affect, the epithelial cells which line the alveoli, evaluating the roles played by metal transporting/binding proteins. The key aims are:1. investigate modulation of metal transporters and metal binding-proteins in response to vanadium and nickel exposure2. investigate accumulation of vanadium and nickel in exposed cells, and effects on the homeostasis of other metals, using state-of-the-art mass spectrometry techniques3. investigate the mechanisms through which the observed effects occur, and the consequences of their dysfunction, using pharmacological and/or genetic techniques.The results of this project will expand our understanding of how cells respond to different metal components of airborne PM, and how PM from different sources may be important in driving lung disease.