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，是健康不良的主要风险因素。然而，我们对PM的不同成分对肺的影响的了解，这涉及到PM的来源，是穷人。这对于理解为什么某些类型的PM可能比其他类型的更具毒性很重要。我们特别感兴趣的是PM中的金属如何驱动肺部疾病（如特发性肺纤维化）的发展和恶化。我们小组最近的工作表明，与航运相关的超细PM（PM的最小尺寸部分）富含钒和镍，并且这种PM以及单独的钒和镍对暴露的细胞产生多种影响。我们还观察到与来自不同来源的颗粒中的其他过渡金属相关的影响，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）的稳态，以及如果这失败的后果。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，如何差异积累，并影响，肺泡上皮细胞，评估金属转运/结合蛋白发挥的作用。主要目标是：1.研究金属转运蛋白和金属结合蛋白对钒和镍的反应2.研究钒和镍在暴露细胞中的积累，以及对其他金属稳态的影响，使用最先进的质谱技术3。研究机制，通过观察到的影响发生，和他们的功能障碍的后果，使用药理学和/或遗传技术。该项目的结果将扩大我们的理解细胞如何响应空气中PM的不同金属成分，以及来自不同来源的PM如何可能是重要的驱动肺部疾病。

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.