Back to search

FRIMEDBIO-Fri med.,helse,biol

Multiomic 4-dimensional identification of novel treatment targets for bile duct inflammation

Alternative title: Multimodal 4-dimensjonal identifisering av nye angrepspunkter for behandling av inflammatoriske gallegangssykdommer

Awarded: NOK 12.0 mill.

Primary sclerosing cholangitis (PSC) is a severe and chronic bile duct disorder without medical treatment. Therefore, there is a critical need for new targets for treatment, to define these properly an increased understanding of the disease process is needed. In general, development of disease is dependent upon the interaction of a range of different biological processes at the same time. In this project we will examine several of these processes simultaneously using several novel and innovative techniques. We will determine the different cells believed to drive the diseases process with regards to active genes and localization in the tissue along with development over time in parallel and integrate this information with advanced algorithms and computing approaches. This approach contrasts traditional strategies that have sought to determine the disease process normally at one time point without taking the spatial development in the tissue into account. In our analyses, we will examine both mouse models of bile duct inflammation and human PSC. This will allow us to identify common concepts that we will then treat in the animal models. Taken together the knowledge gained from the interacting cells in the human diseased tissue and the experience from treatment in the animal models can serve as a guide for developing future treatment for human inflammatory bile duct disorders such as PSC.

Biological processes are highly dynamic and require strict regulation of spatial and temporal interactions amongst the genome, transcriptome and proteome. Perturbations of a single biological layer (‘ome’) can impair cellular function and cause disease, but how the collective alterations influencing the onset and severity of pathogenesis remain poorly understood. To better delineate these overarching processes, experimental approaches integrating molecular, cellular, spatial and temporal findings are needed and hold strong potential for identifying critical pathways that maintain health and prevent disease. Traditional strategies seeking to phenotype disease processes are often (1) low-throughput and limited to a handful of pre-selected markers or (2) imprecise and lacking sufficient resolution to distinguish general disease signatures from rare pathogenic signals. To overcome these constraints, we will use complementary molecular, cellular, spatial, and temporal methodologies to study liver pathology in 4-dimensions and specifically address the process of immune-mediated bile duct destruction in the chronic inflammatory bile duct disease primary sclerosing cholangitis (PSC). By applying cutting-edge single-cell RNA sequencing, spatial transcriptomics, tissue clarification and 3D immunohistochemistry histology alongside organoid co-cultures and murine experimental models, we aim to pinpoint the key interactions that govern the health and destruction of liver bile ducts from pre-inflammation to end-stage PSC (i.e. PSC interactome) and target these interaction in preclinical animal models. Our approach of combining unbiased, high-resolution multiomics with robust functional approaches will greatly improve upon previous efforts of establishing the PSC interactome and aims to define the important biological networks underlying biliary inflammation which are amendable to intervention.

Funding scheme:

FRIMEDBIO-Fri med.,helse,biol