Concept development for mechanistic prediction of material-induced fibrosis and blood coagulation initiation (uCellnNet)

BACKGROUND Every year, 7 million people die due to inhalation of particulate matter in air pollution causing severe chronic inflammation-related diseases, including pulmonary fibrosis. With increasing amounts of man-made nanoparticles introduced to the market and into the environment, inhalation hazard is constantly increasing. To mitigate the risk, efficient nanotoxicological assessment solutions are required. PROBLEM Efficient prediction of chronic inflammation-related diseases is currently hindered by the lack of mechanistic understanding and the current toxicological assessment framework. Recently, 200 man-years have been spent in our discovery of a mechanism responsible for triggering chronic inflammation. To understand the development of even more complex diseases, such as fibrosis, in a much shorter time, a paradigm shift in mechanism discovery, in an animal-free fashion, is absolutely necessary. AIM The uttermost goal of the proposed project is to develop the paradigm-shifting concept of high-throughput identification of the causally connected network of molecular key events and validate it in the case of nanomaterial-induced fibrosis. SOLUTION To foster mechanistic discoveries of disease development, we propose a novel uCellnNet concept, by which we aim to disentangle a response of a natively complex tissue with an entangled network of interactions and overwhelming molecular events among multiple cell types into a network of pairs of individual cell types that exhibit different modes of interactions. For high-throughput monitoring of the latter in real-time, the glass-chip cell-populated device with microscale features - uCellnNet Interaction Mode Inspector - will be developed. Finally, we will validate the here proposed uCellnNet concept on a hypothetical pathway of the development of fibrosis, involving the three key cell types (pulmonary epithelial cells, macrophages, and fibroblasts). TEAM STRENGTH To achieve such an ambitious goal we gathered a multidisciplinary team that has previously already contributed to the discovery of a mechanism of nanoparticle-induced chronic inflammation, published in the prestigious journal Advanced Materials (IF 27). The team consists of top-level experts in advanced high-resolution live-cell imaging, toxicology of inhaled nanomaterials, systems biology, lipid regulation of coagulation enzymes, artificial intelligence guided image analysis, and microscale glass substrate prototyping, thus assuring the project feasibility. IMPACT (Scientific, social, economic) If successful, this project will directly impact the understanding of the development of fibrosis. In addition, uCellnNet concept can certainly boost mechanistic research of early molecular events and their causal connections in the development of nanoparticle-induced diseases and chronic diseases in general, which can be implemented in future regulatory frameworks much faster. This can in turn facilitate high-throughput animal-free toxicological assessment and prediction of nanomaterial safety. Thus, this project directly supports the safe introduction of various powders, microscale materials, and nanomaterials into the everyday market, affecting chemical, nanotech, and electronic industry sectors.