OrganoidTox: Modeling airborne toxin-induced perturbations in cell circuits and their effect on respiratory health

• Applicant: Dr. Carola Voss
• Subject Area: Toxicology, Laboratory Medicine
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 530370007

Airborne toxins cause respiratory health problems globally, contributing to chronic lung diseases such as chronic obstructive pulmonary disease, pulmonary fibrosis, asthma, and lung cancer, with millions of premature deaths worldwide. The effects of mixed ambient toxins and influence of sex and genetic predisposition are particularly important to respiratory health. The underlying cell circuits and molecular modes of action (MoAs) that cause the damage are largely unknown. Current methodologies for respiratory toxicology mainly involve animal experiments, but they suffer from ethical, cost- and species- related difficulties. In vitro assays, high-throughput screening, and computational models and their combination are new approach methodologies (NAMs) for respiratory hazard assessment that are faster, cheaper, and more reliable than animal testing and increasingly used for regulatory decision-making and read-across. Lung organoids are in vitro models that resemble the cellular physiological and structural features of the lung. Organoids can be generated from patient-derived induced pluripotent stem cells (iPSCs) and provide a human organotypic, disease-specific, and even personalized approach for respiratory hazard assessment. Advanced organotypic models encompassing multiple responsive cells allow for the investigation of cell circuits in a controlled, reproducible and manipulable environment and provide a more accurate understanding of airborne toxin-induced MoAs. I propose to identify lung organoids as a NAM to investigate cell circuits of airborne toxins to replace animal experiments. First, I will use a multi-omic approach that deciphers the underlying MoAs of airborne toxins using immuno-competent murine lung organoids. Subsequently, I aim to translate MoAs for airborne toxins into iPSC-human lung organoids and expand to climate change-relevant ozone co-exposures investigating novel cell circuits. Lastly, I will look into genetic and epigenetic changes with sex differences induced by chronic exposure to mixed airborne toxins. As overarching aim, I will establish an in vivo-anchored translational interspecies pipeline based on lung organoids predicting human hazard, called Organotypic ToxAtlas. This novel mapping approach for cell circuits will lead to a comprehensive toxicological response atlas forming the basis for predictive toxicology with lung organoids. I propose an innovative NAM reflecting the 3Rs strategy to investigate respiratory health affected by airborne toxins. The use of lung organoids offers mechanistic insight, manipulation of cell circuits, inhibitor studies with increased relevance to human physiology. The project's results have the potential to provide a comprehensive toxicological response atlas that will form the basis for predictive toxicology with lung organoids. Ultimately, this will lead to the development of future therapeutic strategies for and prevention of respiratory diseases caused by airborne toxins.

• DFG Programme: Independent Junior Research Groups