Molecular pathogenesis and signaling pathways: identification of therapeutic targets in primary sclerosing cholangitis (PSC)

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Primary sclerosing cholangitis (PSC) is a serious inflammatory liver disease leading to liver cirrhosis, cancer, death or liver transplantation. Currently, there is no treatment available to alter the progressive nature of this disease. The pathogenesis of PSC is unknown, but a strong association with inflammatory bowel disease points to the contribution of immune dysregulation at mucosal surfaces. Within the Clinical Research Unit 306 (CRU "Primary Sclerosing Cholangitis") we are investigating the pathogenesis of PSC since the beginning of 2016. Acquisition of experimental data and human biosamples within the first two years of funding enable us now to decipher the molecular pathways leading to liver and intestinal pathology in PSC. We have revealed disease specific changes using immune-phenotyping of liver infiltrating and peripheral blood mononuclear cells by flow cytometry, but this method has the limitation that only few factors can be analyzed at a time in a biased approach. Thus, we aim here to deepen our knowledge using single cell RNA-sequencing, which allows us unbiased single cell analysis on a transcriptional level at a resolution, which has not been possible so far. Applying this novel technique on paired liver and blood derived mononuclear cells will allow us to characterize immune cells potentially involved in disease pathogenesis, and to identify disease specific cellular targets as well as mechanisms which increase homing to and retention of inflammatory cells in the liver. These analyses will be complemented by bulk liver transcriptome analyses from biopsies of patients at different stages of disease as well as from intestinal biopsies in order to identify drugable signaling pathways in immune and non-immune cells. Human samples from liver and intestine are ready to be analyzed and single cell sequencing will be performed within the first year of this application. Data integration and analysis will benefit from the experience of co-applicant SB, who is director of the Institute of Medical Systems Biology at the UKE.