LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

Overview

In one in five people with NAFLD, the functioning liver cells, the hepatocytes, are replaced by connective tissue. Eventually this fibrosis becomes irreversible. In this state the liver is like a ‘scar that never heals’. Through it, the liver loses many of its vital functions. LiSyM-Pillar II wants to know more about which factors promote fibrosis and the conditions under which fibrosis becomes irreversible How can fibrosis be diagnosed as early as possible? Researchers in the pillar are also developing anti-fibrotic drugs, but these are not yet available.

Programme: LiSyM: Liver Systems Medicine

SEEK ID: https://seek.lisym.org/projects/4

Public web page: http://www.lisym.org/our-work/pillar-research

Organisms: Mus musculus, Rattus rattus, Rattus norvegicus, Homo sapiens

FAIRDOM PALs: Janine Koehncke, Annika Schneider, Daniel Lill, Seddik Hammad, Matthias Reichert

Project start date: 1st Jan 2016

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Claire Barbieux

Projects: LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF), LiSyM network

Institutions: Deutsches Krebsforschungszentrum

Johannes Bausch : inactive since 2018-05-16

Projects: LiSyM Core Infrastructure and Management (LiSyM-PD), LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar I: Early Metabolic Injury (LiSyM-EMI), LiSyM Pillar IV: Liver Function Diagnostics (LiSyM-LiFuDi), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF), LiSyM network, LiSyM Scientific Leadership Team (LiSyM-LT)

Institutions: University of Freiburg - Institute of Physics, LiSyM programme directorate

https://orcid.org/0000-0002-1003-1682
Alain Becam adminproject_administrator

Projects: LiSyM network, LiSyM-Krebs, LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Core Infrastructure and Management (LiSyM-PD)

Institutions: HITS gGmbH

Marie-Luise Berres

Projects: LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM network

Institutions: RWTH Aachen University Hospital - Department of Internal Medicine III

Johannes Bode

Projects: LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF), LiSyM network, LiSyM-Krebs Partnering, LiSyM-Krebs

Institutions: Universitätsklinikum Düsseldorf - Klinik für Gastroenterologie, Hepatologie und Infektiologie

LiSyM: Liver Systems Medicine

Liver Systems Medicine : striving to develop non-invasive methods for diagnosing and treating NAFLD by combining mathematical modeling and biological research. LiSyM, is a multidisciplinary research network, in which molecular and cell biologists, clinical researchers, pharmacologists and experts in mathematical modeling examine the liver in its entirety. LiSyM research focuses on the metabolic liver disease non-alcoholic fatty liver disease (NAFLD), which includes non-alcoholic steatohepatitis ...

Projects: LiSyM Core Infrastructure and Management (LiSyM-PD), LiSyM Pillar I: Early Metabolic Injury (LiSyM-EMI), LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF), LiSyM Pillar IV: Liver Function Diagnostics (LiSyM-LiFuDi), Model Guided Pharmacotherapy In Chronic Liver Disease (LiSyM-MGP), Molecular Steatosis - Imaging & Modeling (LiSyM-MSIM), The Hedgehog Signalling Pathway (LiSyM-JGMMS), Multi-Scale Models for Personalized Liver Function Tests (LiSyM-MM-PLF), LiSyM PALs, Project Management PTJ, LiSyM network, LiSyM Scientific Leadership Team (LiSyM-LT)

Web page: https://www.lisym.org/

LiSyM Pillar II: Chronic Liver Disease Progression
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
No description specified

Submitter: Martin Golebiewski

Studies: No Studies

Assays: No Assays

Julia/Yan
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

Pillar II dooley

Submitter: Seddik Hammad

Studies: CCl4 Treatment in mice

Assays: Metabolic CCl4

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CCl4 Treatment in mice
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
No description specified

Submitter: Seddik Hammad

Investigation: Julia/Yan

Assays: Metabolic CCl4

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Metabolic CCl4
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
No description specified

Submitter: Seddik Hammad

Assay type: Proteomics

Technology type: FACS

Investigation: Julia/Yan

Study: CCl4 Treatment in mice

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Robustness and applicability of transcription factor and pathway analysis tools on single-cell RNA-seq data
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

GitHub repository containing the analysis code

Creator: Christian Holland

Submitter: Christian Holland

External Link
Transfer of regulatory knowledge from human to mouse for functional genomics analysis
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

GitHub repository that contains all analyses scripts to reproduce the results reported in "Transfer of regulatory knowledge from human to mouse for functional genomics analysis"

Creator: Christian Holland

Submitter: Christian Holland

Movies for quantification
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
No description specified

Creator: Seddik Hammad

Submitter: Seddik Hammad

TextBookData
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
No description specified

Creators: None

Submitter: Seddik Hammad

F4-80
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
No description specified

Creators: None

Submitter: Seddik Hammad

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Intermediate TGFß signaling model
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

not yet calibrated, not yet reduced

Creators: Daniel Lill, Viktor Makarenko

Submitter: Daniel Lill

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SOP RNA Isolation from healthy and fatty liver
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF)
No description specified

Creator: Sonja Kleeschulte

Submitter: Sonja Kleeschulte

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SOP FACS analysis of Macrophage population in healthy and fatty liver
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF)

Non-parenchymal liver cells are isolated and staining for FACS analysis

Creator: Sonja Kleeschulte

Submitter: Sonja Kleeschulte

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SOP Immunhistochemistry Mac2 staining
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF)

Macrophage staining in paraffin-embedded tissue

Creator: Sonja Kleeschulte

Submitter: Sonja Kleeschulte

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Transcriptomic Cross‐Species Analysis of Chronic Liver Disease Reveals Consistent Regulation Between Humans and Mice
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

Abstract

Not specified

Authors: Christian H. Holland, Ricardo O. Ramirez Flores, Maiju Myllys, Reham Hassan, Karolina Edlund, Ute Hofmann, Rosemarie Marchan, Cristina Cadenas, Jörg Reinders, Stefan Hoehme, Abdel‐latif Seddek, Steven Dooley, Verena Keitel, Patricio Godoy, Brigitte Begher‐Tibbe, Christian Trautwein, Christian Rupp, Sebastian Mueller, Thomas Longerich, Jan G. Hengstler, Julio Saez‐Rodriguez, Ahmed Ghallab

Date Published: 28th Aug 2021

Publication Type: Journal

Data-driven personalization of a physiologically based pharmacokinetic model for caffeine: A systematic assessment
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

Abstract (Expand)

Physiologically based pharmacokinetic (PBPK) models have been proposed as a tool for more accurate individual pharmacokinetic (PK) predictions and model-informed precision dosing, but their application … in clinical practice is still rare. This study systematically assesses the benefit of using individual patient information to improve PK predictions. A PBPK model of caffeine was stepwise personalized by using individual data on (1) demography, (2) physiology, and (3) cytochrome P450 (CYP) 1A2 phenotype of 48 healthy volunteers participating in a single-dose clinical study. Model performance was benchmarked against a caffeine base model simulated with parameters of an average individual. In the first step, virtual twins were generated based on the study subjects' demography (height, weight, age, sex), which implicated the rescaling of average organ volumes and blood flows. The accuracy of PK simulations improved compared with the base model. The percentage of predictions within 0.8-fold to 1.25-fold of the observed values increased from 45.8% (base model) to 57.8% (Step 1). However, setting physiological parameters (liver blood flow determined by magnetic resonance imaging, glomerular filtration rate, hematocrit) to measured values in the second step did not further improve the simulation result (59.1% in the 1.25-fold range). In the third step, virtual twins matching individual demography, physiology, and CYP1A2 activity considerably improved the simulation results. The percentage of data within the 1.25-fold range was 66.15%. This case study shows that individual PK profiles can be predicted more accurately by considering individual attributes and that personalized PBPK models could be a valuable tool for model-informed precision dosing approaches in the future.

Authors: Rebekka Fendt, Ute Hofmann, Annika Schneider, Elke Schaeffeler, Rolf Burghaus, Ali Yilmaz, Lars Mathias Blank, Reinhold Kerb, Jan-Frederik Schlender, Matthias Schwab, Lars Kuepfer

Date Published: 30th May 2021

Publication Type: Journal

Liver sinusoidal endothelial cells suppress BMP2 production in response to TGFβ pathway activation
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

Abstract

Not specified

Authors: Silvia Colucci, Sandro Altamura, Oriana Marques, Anne Dropmann, Natalie K. Horvat, Katja Müdder, Seddik Hammad, Steven Dooley, Martina U. Muckenthaler

Date Published: 13th May 2021

Publication Type: Journal

Unexpected Pro-Fibrotic Effect of MIF in Non-Alcoholic Steatohepatitis Is Linked to a Shift in NKT Cell Populations
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

Abstract (Expand)

Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine with anti-fibrotic properties in toxic liver injury models and anti-steatotic functions in non-alcoholic fatty liver … disease (NAFLD) attributed to the CD74/AMPK signaling pathway. As NAFLD progression is associated with fibrosis, we studied MIF function during NAFLD-associated liver fibrogenesis in mice and men by molecular, histological and immunological methods in vitro and in vivo. After NASH diet feeding, hepatic Mif expression was strongly induced, an effect which was absent in Mif∆hep mice. In contrast to hepatotoxic fibrosis models, NASH diet-induced fibrogenesis was significantly abrogated in Mif−/− and Mif∆hep mice associated with a reduced accumulation of the pro-fibrotic type-I NKT cell subpopulation. In vitro, MIF skewed the differentiation of NKT cells towards the type-I subtype. In line with the murine results, expression of fibrosis markers strongly correlated with MIF, its receptors, and markers of NKT type-I cells in NASH patients. We conclude that MIF expression is induced during chronic metabolic injury in mice and men with hepatocytes representing the major source. In NAFLD progression, MIF contributes to liver fibrogenesis skewing NKT cell polarization toward a pro-fibrotic phenotype highlighting the complex, context-dependent role of MIF during chronic liver injury.

Authors: D. Heinrichs, E. F. Brandt, P. Fischer, Janine Koehncke, Theresa H. Wirtz, N. Guldiken, S. Djudjaj, P. Boor, D.Kroy, R. Weiskirchen, Richard Bucala, H.E. Wasmuth, P. Strnad, Christian Trautwein, J. Bernhagen, M. L. Berres

Date Published: 28th Jan 2021

Publication Type: Journal

Robustness and applicability of transcription factor and pathway analysis tools on single-cell RNA-seq data
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM network

Abstract (Expand)

Background Many functional analysis tools have been developed to extract functional and mechanistic insight from bulk transcriptome data. With the advent of single-cell RNA sequencing (scRNA-seq), it … is in principle possible to do such an analysis for single cells. However, scRNA-seq data has characteristics such as drop-out events and low library sizes. It is thus not clear if functional TF and pathway analysis tools established for bulk sequencing can be applied to scRNA-seq in a meaningful way. Results To address this question, we perform benchmark studies on simulated and real scRNA-seq data. We include the bulk-RNA tools PROGENy, GO enrichment, and DoRothEA that estimate pathway and transcription factor (TF) activities, respectively, and compare them against the tools SCENIC/AUCell and metaVIPER, designed for scRNA-seq. For the in silico study, we simulate single cells from TF/pathway perturbation bulk RNA-seq experiments. We complement the simulated data with real scRNA-seq data upon CRISPR-mediated knock-out. Our benchmarks on simulated and real data reveal comparable performance to the original bulk data. Additionally, we show that the TF and pathway activities preserve cell type-specific variability by analyzing a mixture sample sequenced with 13 scRNA-seq protocols. We also provide the benchmark data for further use by the community. Conclusions Our analyses suggest that bulk-based functional analysis tools that use manually curated footprint gene sets can be applied to scRNA-seq data, partially outperforming dedicated single-cell tools. Furthermore, we find that the performance of functional analysis tools is more sensitive to the gene sets than to the statistic used.

Authors: Christian H. Holland, Jovan Tanevski, Javier Perales-Patón, Jan Gleixner, Manu P. Kumar, Elisabetta Mereu, Brian A. Joughin, Oliver Stegle, Douglas A. Lauffenburger, Holger Heyn, Bence Szalai, Julio Saez-Rodriguez

Date Published: 1st Dec 2020

Publication Type: Journal

TGFb in activated hepatic stellate cells as the modulator of collagen accumulation in chronic liver disease
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM network

Jamboree presentation

Creators: Daniel Lill, Viktor Makarenko, Ursula Klingmüller, Jens Timmer

Submitter: Daniel Lill

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CYP2E1 recovery is associated with a pericentral fibrosis pattern after repeated CCl4 insults
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
No description specified

Creator: Seddik Hammad

Submitter: Seddik Hammad

Cellular and nuclear hepatocyte ploidy represent a repository in regenerating livers
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
No description specified

Creator: Seddik Hammad

Submitter: Seddik Hammad

Decreased ECM1 expression is consistent in HCC and correlates with overall survival
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
No description specified

Creator: Seddik Hammad

Submitter: Seddik Hammad

GPNMB as hepatocytic suppressor of steatosis and liver cancer
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
No description specified

Creator: Seddik Hammad

Submitter: Seddik Hammad

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First LiSyM PostDoc and PhD student retreat

The meeting will provide a great opportunity for discussion between modellers, experimentalists and clinicians and to organize and harmonize our future work within the LiSyM network on the grassroot level.

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Start Date: 9th Nov 2017

End Date: 11th Nov 2017

Event Website: https://events.easl.eu/EventPortal/Information/EventInformation.aspx?EventInformationPageCode=HOME&EventCode=nafld2017

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18th International Conference on Systems Biology (ICSB 2017)

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Abstract submission deadline: May 13th, 2017

Start Date: 6th Aug 2017

End Date: 12th Aug 2017

Event Website: http://www.cpe.vt.edu/icsb2017/

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International Conference on Systems Biology of Human Disease (SBHD)

The International Conference on Systems Biology of Human Disease (SBHD) is a transatlantic event and communication platform for scientific exchange that takes place alternately between the United States and Germany.

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Start Date: 5th Jul 2017

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Joint LiSyM & ERASysAPP Data Management PALs Meeting

This event is a jointly organized Data Management PALs Meeting that involves PALs from the German LiSyM (Liver Systems Medicine) network and from the ERASysAPP (ERA-Net for Systems Biology Applications) initiative. PALs (Project Area Liaisons) are the front line experts of the data management teams of these projects. They act as data management advocates and help gathering user requirements and testing potential data management solutions. An important part of the meeting will be to gather the ...

Start Date: 2nd May 2017

End Date: 3rd May 2017

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Country:  Germany

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