EN
Project - A06:
The roles of short expressed peptides and cell type composition in autoimmune liver inflammation
Project leaders:
Prof. Dr. med. Norbert Hübner &
Prof. Dr. med. Christoph Schramm
Summary
Chronic damage to the liver such as immune-mediated and autoimmune inflammation results in excessive extracellular matrix production with consequential fibrosis and, in many cases, ultimately leads to cirrhosis. The mechanisms of uncontrolled inflammation and progressive fibrosis in the autoimmune liver diseases (AILD) primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) remain incompletely understood.
To gain new insights into the pathogenesis of AILD, we will study human hepatic translational events by measuring genome-wide active translation with ribosome profiling (Ribo-seq). This will allow us to identify novel short open reading frames (sORFs)-encoded peptides (SEPs) in RNA regions previously classified as non-coding (ncRNA). By comparing patients and controls, we will be able to detect disease-specific expression of annotated and novel peptides that may lead to the creation of new self-antigens, breaking of self-tolerance, triggering of autoimmune B and T cell responses, and / or modulation of inflammation or fibrosis. Since novel SEPs may have specialised roles in the function of specific cell types, knowledge about their expression across specific cell types will aid in the identification of their functional relevance. To address this, we will characterise hepatic cell types and states, expression networks, cellular circuits and spatial location by single-cell and spatial profiling approaches.
Moreover, by building a single-cell atlas for AILD, we will discern fundamental causes of maladaptive hepatic immune regulation, characterise heterogeneous cellular responses and infer new strategies to limit them. The analysis will allow us to identify and characterise rare subpopulations of intrahepatic cells that represent as little as 1% of the main population and harbour potential importance for liver homeostasis and disease development. Furthermore, it will unravel the heterogeneity, composition, potential function and spatial location of hepatic parenchymal and non-parenchymal subpopulations in AILD patients. The analysis of biopsy samples from an early stage of AILD in comparison to late stages will provide insight into initiating factors of the diseases and will show how fibrosis develops and progresses over time. Concurrently, computational tools for single-cell data analysis have been developed to follow dynamic processes such as cell differentiation and activation as well as explore interactions between cell populations based on their repertoire of ligands and receptors. While the emphasis of our studies will lie on PSC, the CRC network will enable us to extend our analyses to other AILD as a next step and various liver diseases in the future.
Project plan
We hypothesise that novel unannotated SEP are generated in chronically inflamed liver tissue of AILD patients that i) will have a modulatory effect on the disease process and ii) may expand the immunopeptidome in AILD. Moreover, we hypothesise that hepatic remodeling differs for each AILD etiology and correlates to changes in cell subpopulation prevalence and in cell type-specific gene expression. The molecular and cellular drivers underlying autoimmune and immune-mediated chronic liver inflammation and fibrosis remain incompletely understood. This project will focus on the identification of new AILD-specific SEPs. Moreover, we will define the cellular and transcriptional heterogeneity of AILD with single-cell sequencing approaches. Our long-term goal is to understand the function of novel disease-specific SEPs and to investigate the functional relevance of cell type-specific changes in AILD.
In order to test this hypothesis, our work programme has the following work packages (WP):
WP1: To detect, to validate and to characterise short ORF-encoded peptides (SEPs) in AILD.
WP2: To define hepatic cell type composition and SEP-expression in AILD.
WP3: To characterise candidate SEPs and their role in the immunopeptidome, cell function and interaction.
Project related publications
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# equally contributing authors