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

Overview

Chronic liver diseases (CLD) progression leads to cirrhosis, often cancer, and ultimately to organ failure and death. Because of the complexity of this scenario, a Systems Medicine approach is chosen to develop strategies to better characterize progression and resolution of fibrosis. Pillar II aims to define key molecular mechanisms and structural changes in tissue architecture during the progression of CLD by visualizing and quantifying at a cellular level, tissue and organ scale.

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

Public web page: Not specified

Organisms: Mus musculus, Rattus rattus, Rattus norvegicus

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

Project created: 21st Feb 2017

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Claire Barbieux

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

Institutions: Deutsches Krebsforschungszentrum

Marie-Luise Berres

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

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

Johannes Bode

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

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

Lorenza D'Alessandro

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

Institutions: Deutsches Krebsforschungszentrum

Helen Desmond project_administratorasset_housekeeper

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

Institutions: LiSyM programme directorate

LiSyM Pillar II: Chronic Liver Disease Progression
Chronic Liver Disease Progression (LiSyM-DP - Pillar II)
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Snapshots: No snapshots

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

Pillar II dooley

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

Person responsible: Seddik Hammad

Snapshots: No snapshots

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

Contributor: Seddik Hammad

Assay type: Proteomics

Technology type: FACS

Snapshots: No snapshots

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

Creator: Seddik Hammad

Contributor: Seddik Hammad

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

Creators: None

Contributor: Seddik Hammad

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

Creators: None

Contributor: Seddik Hammad

F4/80 staining after acute damage by CCl4
Chronic Liver Disease Progression (LiSyM-DP - Pillar II)
No description specified

Creators: None

Contributor: Seddik Hammad

Voids in CCl4
Chronic Liver Disease Progression (LiSyM-DP - Pillar II)

Voids in CCl4

Creators: None

Contributor: Seddik Hammad

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

Creator: Sonja Kleeschulte

Contributor: Sonja Kleeschulte

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

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

Creator: Sonja Kleeschulte

Contributor: Sonja Kleeschulte

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

Macrophage staining in paraffin-embedded tissue

Creator: Sonja Kleeschulte

Contributor: Sonja Kleeschulte

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Benchmark and integration of resources for the estimation of human transcription factor activities
Chronic Liver Disease Progression (LiSyM-DP - Pillar II), LiSyM network

Abstract (Expand)

The prediction of transcription factor (TF) activities from the gene expression of their targets (i.e., TF regulon) is becoming a widely used approach to characterize the functional status of transcriptional … regulatory circuits. Several strategies and data sets have been proposed to link the target genes likely regulated by a TF, each one providing a different level of evidence. The most established ones are (1) manually curated repositories, (2) interactions derived from ChIP-seq binding data, (3) in silico prediction of TF binding on gene promoters, and (4) reverse-engineered regulons from large gene expression data sets. However, it is not known how these different sources of regulons affect the TF activity estimations and, thereby, downstream analysis and interpretation. Here we compared the accuracy and biases of these strategies to define human TF regulons by means of their ability to predict changes in TF activities in three reference benchmark data sets. We assembled a collection of TF–target interactions for 1541 human TFs and evaluated how different molecular and regulatory properties of the TFs, such as the DNA-binding domain, specificities, or mode of interaction with the chromatin, affect the predictions of TF activity. We assessed their coverage and found little overlap on the regulons derived from each strategy and better performance by literature-curated information followed by ChIP-seq data. We provide an integrated resource of all TF–target interactions derived through these strategies, with confidence scores, as a resource for enhanced prediction of TF activities.

Authors: Luz Garcia-Alonso, Christian Holland, Mahmoud M. Ibrahim, Denes Turei, Julio Saez-Rodriguez

Date Published: 1st Aug 2019

Journal: Genome Res.

Robustness and applicability of functional genomics tools on scRNA-seq data
Chronic Liver Disease Progression (LiSyM-DP - Pillar II), LiSyM network

Abstract (Expand)

Many tools have been developed to extract functional and mechanistic insight from bulk transcriptome profiling 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, low library sizes and a comparatively large number of samples/cells. It is thus not clear if functional genomics tools established for bulk sequencing can be applied to scRNA-seq in a meaningful way. To address this question, we performed benchmark studies on in silico and in vitro single-cell RNA-seq data. We included the bulk-RNA tools PROGENy, GO enrichment and DoRothEA that estimate pathway and transcription factor (TF) activities, respectively, and compared them against the tools AUCell and metaVIPER, designed for scRNA-seq. For the in silico study we simulated single cells from TF/pathway perturbation bulk RNA-seq experiments. Our simulation strategy guarantees that the information of the original perturbation is preserved while resembling the characteristics of scRNA-seq data. We complemented the in silico data with in vitro scRNA-seq data upon CRISPR-mediated knock-out. Our benchmarks on both the simulated and real data revealed comparable performance to the original bulk data. Additionally, we showed that the TF and pathway activities preserve cell-type specific variability by analysing a mixture sample sequenced with 13 scRNA-seq different protocols. Our analyses suggest that bulk functional genomics tools can be applied to scRNA-seq data, outperforming dedicated single cell tools. Furthermore we provide a benchmark for further methods development by the community.

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

Date Published: No date defined

Journal: Not specified

Cooperative and distinct functions of MK2 and MK3 in the regulation of the macrophage transcriptional response to lipopolysaccharide.
Chronic Liver Disease Progression (LiSyM-DP - Pillar II), Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF - Pillar III)

Abstract (Expand)

The p38(MAPK) downstream targets MAPKAP kinases (MK) 2 and 3 are critical for the regulation of the macrophage response to LPS. The extents to which these two kinases act cooperatively and distinctly … in regulating LPS-induced inflammatory cytokine expression are still unclear. To address this uncertainty, whole transcriptome analyses were performed using bone marrow-derived macrophages (BMDM) generated from MK2(-/-) or MK2/3(-/-) animals and their wild-type littermates. The results suggest that in BMDM, MK2 and MK3 not only cooperatively regulate the transcript expression of signaling intermediates, including IL-10, IL-19, CXCL2 and the IL-4 receptor (IL-4R)alpha subunit, they also exert distinct regulatory effects on the expression of specific transcripts. Based on the differential regulation of gene expression by MK2 and MK3, at least six regulatory patterns were identified. Importantly, we confirmed our previous finding, which showed that in the absence of MK2, MK3 negatively regulates IFN-beta. Moreover, this genome-wide analysis identified the regulation of Cr1A, NOD1 and Serpina3f as similar to that of IFN-beta. In the absence of MK2, MK3 also delayed the nuclear translocation of NFkappaB by delaying the ubiquitination and subsequent degradation of IkappaBbeta, reflecting the substantial plasticity of the response of BMDM to LPS.

Authors: Christian Ehlting, J. Rex, U. Albrecht, R. Deenen, C. Tiedje, K. Kohrer, O. Sawodny, M. Gaestel, D. Haussinger, Johannes Bode

Date Published: 30th Jul 2019

Journal: Sci Rep

ECM1 Prevents Activation of Transforming Growth Factor beta, Hepatic Stellate Cells, and Fibrogenesis in Mice.
Chronic Liver Disease Progression (LiSyM-DP - Pillar II), LiSyM network

Abstract (Expand)

BACKGROUND & AIMS: Activation of transforming growth factor beta (TGFB) promotes liver fibrosis by activating hepatic stellate cells (HSCs), but the mechanism of TGFB activation are not clear. We … investigated the role of extracellular matrix protein 1 (ECM1), which interacts with extracellular and structural proteins, in TGFB activation in livers of mice. METHODS: We performed studies with e C57BL/6J mice (controls), ECM1-knockout (ECM1-KO) mice, and mice with hepatocyte-specific knockout of EMC1 (ECM1Deltahep). ECM1 or soluble TGFB receptor 2 (TGFBR2) were expressed in livers of mice following injection of an adeno-associated virus vector. Liver fibrosis was induced by carbon tetrachloride (CCl4) administration. Livers were collected from mice and analyzed by histology, immunohistochemistry, in situ hybridization, and immunofluorescence analyses. Hepatocytes and HSCs were isolated from livers of mice and incubated with ECM1; production of cytokines and activation of reporter genes were quantified. Liver tissues from patients with viral or alcohol-induced hepatitis (with different stages of fibrosis) and individuals with healthy liver were analyzed by immunohistochemistry and in situ hybridization. RESULTS: ECM1-KO mice spontaneously developed liver fibrosis and died by 2 months of age without significant hepatocyte damage or inflammation. In liver tissues of mice, we found that ECM1 stabilized extracellular matrix-deposited TGFB in its inactive form by interacting with alphav integrins to prevent activation of HSCs. In liver tissues from patients and in mice with CCl4-induced liver fibrosis, we found an inverse correlation between level of ECM1 and severity of fibrosis. CCl4-induced liver fibrosis was accelerated in ECM1Deltahep mice compared with control mice. Hepatocytes produced the highest levels of ECM1 in livers of mice. Ectopic expression of ECM1 or soluble TGFBR2 in liver prevented fibrogenesis in ECM1-KO mice and prolonged their survival. Ectopic expression of ECM1 in liver also reduced the severity of CCl4-induced fibrosis in mice. CONCLUSIONS: ECM1, produced by hepatocytes, inhibits activation of TGFB and its activation of HSCs to prevent fibrogenesis in mouse liver. Strategies to increase levels of ECM1 in liver might be developed for treatment of fibrosis.

Authors: W. Fan, T. Liu, W. Chen, Seddik Hammad, T. Longerich, Y. Fu, N. Li, Y. He, C. Liu, Y. Zhang, Q. Lian, Jieling Zhao, C. Yan, L. Li, C. Yi, Z. Ling, L. Ma, Jieling Zhao, H. Xu, P. Wang, M. Cong, H. You, Z. Liu, Y. Wang, J. Chen, D. Li, L. Hui, Steven Dooley, J. Hou, J. Jia, B. Sun

Date Published: 27th Jul 2019

Journal: Gastroenterology

Mapping connections in signaling networks with ambiguous modularity.
Chronic Liver Disease Progression (LiSyM-DP - Pillar II)

Abstract (Expand)

Modular Response Analysis (MRA) is a suite of methods that under certain assumptions permits the precise reconstruction of both the directions and strengths of connections between network modules from … network responses to perturbations. Standard MRA assumes that modules are insulated, thereby neglecting the existence of inter-modular protein complexes. Such complexes sequester proteins from different modules and propagate perturbations to the protein abundance of a downstream module retroactively to an upstream module. MRA-based network reconstruction detects retroactive, sequestration-induced connections when an enzyme from one module is substantially sequestered by its substrate that belongs to a different module. Moreover, inferred networks may surprisingly depend on the choice of protein abundances that are experimentally perturbed, and also some inferred connections might be false. Here, we extend MRA by introducing a combined computational and experimental approach, which allows for a computational restoration of modular insulation, unmistakable network reconstruction and discrimination between solely regulatory and sequestration-induced connections for a range of signaling pathways. Although not universal, our approach extends MRA methods to signaling networks with retroactive interactions between modules arising from enzyme sequestration effects.

Authors: Daniel Lill, O. S. Rukhlenko, A. J. Mc Elwee, E. Kashdan, Jens Timmer, B. N. Kholodenko

Date Published: 1st Jun 2019

Journal: NPJ Syst Biol Appl

Pillar II presentations (one file) - Jamboree, Leipzig2019
Chronic Liver Disease Progression (LiSyM-DP - Pillar II)
No description specified

Creator: Seddik Hammad

Contributor: Seddik Hammad

Pillar II: Outline poster-Jamboree2019-Leipzig
Chronic Liver Disease Progression (LiSyM-DP - Pillar II), LiSyM network
No description specified

Creator: Seddik Hammad

Contributor: Seddik Hammad

AG Dooley Poster- Jamboree2019-Leipzig
Chronic Liver Disease Progression (LiSyM-DP - Pillar II), LiSyM network
No description specified

Creator: Seddik Hammad

Contributor: Seddik Hammad

07052019-V1-Pillar 2: TissueScale Presentation (Seddik/Dirk)
Chronic Liver Disease Progression (LiSyM-DP - Pillar II)
No description specified

Creator: Seddik Hammad

Contributor: Seddik Hammad

07052019-V1-Pillar 2: TissueScale Presentation (Seddik/Dirk)
Chronic Liver Disease Progression (LiSyM-DP - Pillar II)
No description specified

Creator: Seddik Hammad

Contributor: 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.

Start Date: 20th Nov 2017

End Date: 22nd Nov 2017

Event Website: Not specified

Country:  Germany

City: Hünfeld

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.

SBHD 2017 is continuing a conference series launched by Peter Sorger and colleagues from Harvard Medical School in 2008. The conference focus is on mammalian systems biology, particularly on its application to human disease and therapy.

Start Date: 5th Jul 2017

End Date: 7th Jul 2017

Event Website: http://www.sbhd-conference.org/2017/index.php

Country:  Germany

City: Heidelberg

First EASL Nonalcoholic Fatty Liver Disease (NAFLD) Summit: Target-oriented approach to Diagnosis and Pharmacotherapy of Nonalcoholic Steatohepatitis (NASH), a dialogue between Academia and Industry

This summit will cover both the basic and translational / clinical aspects of NAFLD, with a specific focus on novel drug target and prognostic signature development.

Key sessions include all crucial pathophysiological aspects currently known to affect development and progression of NAFLD, such as "lipid metabolism and lipotoxicity" and "insulin resistance, insulin and hormonal signaling". Furthermore, oxidative stress, ER stress, and mitochondrial dysfunction will be addressed. On the second day,
...

Start Date: 9th Nov 2017

End Date: 11th Nov 2017

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

Country:  Italy

City: Rome

18th International Conference on Systems Biology (ICSB 2017)

ICSB continues to be the flagship conference of the International Society for Systems Biology (ISSB). The conference will cover a variety of themes from Fundamental Biological Sciences, Network Analysis, to Metabolic Engineering and Cancer Biology. The conference will also include a variety of engaging plenary lectures, parallel sessions, poster sessions, and interactive networking opportunities.

Abstract submission deadline: May 13th, 2017

Start Date: 6th Aug 2017

End Date: 12th Aug 2017

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

Country:  United States

City: Blacksburg, Virginia

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
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Start Date: 2nd May 2017

End Date: 3rd May 2017

Event Website: https://fairdomhub.org/events/64

Country:  Germany

City: 36088 Hünfeld bei Fulda

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