The inflammatory effects of polyaromatic hydrocarbon air pollutant phenanthrene on cardiovascular dysfunction assessed using single nucleus sequencing

The WHO estimates that 99% of the global population breathes air exceeding guideline pollution limits, with 70% of all air pollution deaths attributed to cardiovascular disease. Phenanthrene, a polyaromatic hydrocarbon (PAH) component of air pollution, has been identified as the chief contributor to PAH-induced cardiovascular dysfunction in vitro and in vivo. Phenanthrene exists both in the gas phase and condensed particle phase via adsorption to particulate matter (PM). Translocation of PM2.5 into the bloodstream enables phenanthrene to enter systemic circulation and have effects on major organs. Much of the phenanthrene which is ingested or inhaled reaches both the liver, as the main immunological organ. The degree to which pro-inflammatory effects originating from metabolism in the liver contributes to the cardiovascular dysfunction exhibited post-phenanthrene exposure has not yet been fully explored. Here, we will use single nucleus RNA sequencing to identify changes in the cardiovascular and hepatic transcriptomes from mice chronically exposed to different concentrations of phenanthrene via IP injection or ingestion. Heart and liver nuclei from mice of different ages exposed daily to various concentrations of phenanthrene for 6-12 weeks will be sequenced at the single cell level. This will allow us to assess changes in cardiohepatic transcriptomes and differential expression of genes post-phenanthrene exposure. 'Omics analysis will be carried out computationally using ScanPy and Seurat in python and R. In both organs, we suspect key genes involved in pro-inflammatory pathways, fibrosis, metabolic syndrome, oxidative stress, and more will be affected, and we will be able to identify how individual cell types contribute to dysfunction. This understanding is vital to the development of strategies to mitigate phenanthrene exposure risk which undoubtedly contributes to millions of premature deaths around the world as a consequence of air pollution each year.

Aerosol science has a significant impact on a broad range of disciplines, extending from inhaled drug delivery, to combustion science and its health impacts, aerosol assisted routes to materials, climate change, and the delivery of agricultural and consumer products. Estimates of the global aerosol market size suggest it will reach $84 billion/year by 2024 with products in the personal care, household, automotive, food, paints and medical sectors. Air pollution leads to an estimated 30-40,000 premature deaths each year in the UK, and aerosols transmit human and animal infections. More than 12 million people in the UK live with lung disease such as asthma, and the NHS spends ~£5 billion/year on respiratory therapies. Many of the technological, societal and health challenges central to these areas rely on core skills and knowledge of aerosol science. Despite this, an Industrial Workshop and online survey (held in preparation for this bid) highlighted the current doctoral skills gap in aerosol science in the UK. Participating industries reported that only 15% of their employees working with aerosol science at doctoral-level having received any formal training. A CDT in aerosol science, CAS, will fill this skills gap, impacting on all areas of science where core training in aerosol science is crucial.

Impact on the UK aerosol community: Aerosol scientists work across governmental policy, industrial research and innovation, and in academia. Despite the considerable overlap in training needs for researchers working in these diverse sectors, current doctoral training in aerosol science is fragmentary and ad hoc (e.g. the annual Fundamentals of Aerosol Science course delivered by the Aerosol Society). In addition, training occurs within the context of individual disciplines, reinforcing artificial subject boundaries. CAS will bring coherence to training in the core physical and engineering science of aerosols, catalysing new synergies in research, and providing a focal point for training a multidisciplinary community of researchers. Working with the Aerosol Society, we will establish a legacy by providing training resources for future researchers through an online training portal.

Impact on industry and public-sector partners: 45 organisations have indicated they will act as CAS partners with interests in respiratory therapies, public health, materials manufacturing, consumer and agricultural products, instrumentation, emissions and environment. Establishing CAS will deliver researchers with the necessary skills to ensure the UK establishes and sustains a scientific and technical lead in their sectors. Further, it will provide an ideal mechanism for delivering Continuing Professional Development for the existing workforce practitioners. The activity of CAS is aligned to the Industrial Strategy Challenge Fund (e.g. through developing new healthcare technologies and new materials) and the EPSRC Prosperity Outcomes of a productive, healthy (e.g. novel treatments for respiratory disease) and resilient (e.g. adaptations to climate change, air quality) nation, with both the skilled researchers and their science naturally translating to long-lasting impact. Additionally, rigorous training in responsible innovation and ethical standards will lead to aerosol researchers able to contribute to developing: regulatory standards for medicines; policy on air quality and climate geoengineering; and regulations on manufactured nano-materials.

Public engagement: CAS will provide a focal point for engaging the public on topics in aerosol science that affect our daily lives (consumer products, materials) through to our health (inhalation therapeutics, disease transmission and impacts of pollution) and the future of our planet (geoengineering). Supported by a rigorous doctoral level training in aerosol science, this next generation of researchers will be ideally positioned to lead debates on all of these societal and technological challenges.