Ursula Klingmüller

About Ursula Klingmüller:
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SEEK ID: https://seek.lisym.org/people/139

Location:  Germany

Expertise: Not specified

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ORCID: Not specified

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LiSyM-Krebs - Systemmedizinisches Forschungsnetz zur Früherkennung und Prävention von Leberkrebs

LiSyM-Krebs ist ein nationales Forschungsnetz zur Früherkennung und Prävention von Leberkrebs, das unter Verwendung des systemmedizinischen Forschungsansatzes die komplexen, dynamischen Prozesse der Krankheitsprogression analysiert, um ausgehend von den Erkenntnissen aus dem Forschungsnetz LiSyM die Entstehung von Leberkrebs besser zu verstehen, vorherzusagen und im besten Fall sogar zu verhindern. LiSyM-Krebs setzt die erfolgreichen Forschungsaktivitäten der BMBF-Vorgängerprogramme ...

Projects: LiSyM-Krebs Partnering, Forschungsnetzwerk LiSyM-Krebs, SMART-NAFLD, DEEP-HCC network, C-TIP-HCC network

Web page: Not specified

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/

Forschungsnetzwerk LiSyM-Krebs

Forschungsnetzwerk zur Früherkennung und Prävention- LiSyM-Krebs

Ein Netzwerk von Klinikern, Wissenschaftlern und Datenmanagern hat sich zur Aufgabe gemacht, Methoden zu entwickeln, um Patienten mit einem hohen Risiko für ein Leberkarzinom frühzeitig, in Vorstadien der Tumorentwicklung, identifizieren zu können. Gemeinsam bilden sie das „Systemmedizinische Forschungsnetzwerk zur Früherkennung und Prävention von Leberkrebs“, LiSym-Krebs, das vom Bundesministerium für Bildung und Forschung ...

Programme: LiSyM-Krebs - Systemmedizinisches Forschungsnetz zur Früherkennung und Prävention von Leberkrebs

Public web page: Not specified

SMART-NAFLD

SMART-NAFLD : A Systems Medicine Approach to Early Detection and Prevention of Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease

The massive increase in obesity is leading to an alarming rise in non-alcoholic liver disease (NAFLD). This development will lead to a dramatic increase in liver diseases such as hepatocellular carcinoma (HCC). A particular challenge is that NAFLD-associated HCCs, for reasons still unknown, not only occur in association with advanced liver fibrosis/cirrhosis, ...

Programme: LiSyM-Krebs - Systemmedizinisches Forschungsnetz zur Früherkennung und Prävention von Leberkrebs

Public web page: Not specified

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

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 ...

Programme: LiSyM: Liver Systems Medicine

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

Start date: 1st Jan 2016

LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF)

In chronic diseases, at some point the liver can suddenly stop functioning. This is called acute-on-chronic liver failure, or ACLF. This is the leading cause of death in liver patients and is often provoked by the use of transcription or freely available drugs or alcohol abuse. For this condition we need an effective treatment quickly. LiSyM-Pillar III researches the factors that contribute significantly to ACLF. What exactly happens then? Are there any early signs that would enable ACLF to be ...

Programme: LiSyM: Liver Systems Medicine

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

Start date: 1st Jan 2016

LiSyM network

This comprises the whole LiSyM network

Programme: LiSyM: Liver Systems Medicine

Public web page: http://www.lisym.org

Start date: 1st Jan 2016

Deutsches Krebsforschungszentrum

Country:  Germany

City: 69120 Heidelberg

Web page: http://www.dkfz.de

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IFNalpha-induced signaling in Huh7.5 cells
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM network

ODE model describes dynamics of IFNalpha-induced signaling in Huh7.5 cells for a time scale up to 32 hours after stimulation with IFNalpha. The model consists of an IFN receptor model, formation/degradation and cytoplasmic/nuclear shuttling of STAT1-homodimers, STAT1-STAT2-heterodimers and STAT1-STAT2-IRF9 (ISGF3) complexes. On top, formation of feedback proteins STAT1, STAT2, IRF9, USP18, SOCS1, SOCS3 and IRF2 and corresponding influences on IFNalpha signaling dynamics was incorporated. The model ...

Creators: Jens Timmer, Ursula Klingmüller, Daniel Seehofer, Marcus Rosenblatt, Krishna Kumar Tiwari, Frédérique Kok

Submitter: Olga Krebs

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Erythropoietin-driven dynamic proteome adaptations during erythropoiesis prevent iron overload in the developing embryo.
LiSyM network, SMART-NAFLD

Abstract (Expand)

Erythropoietin (Epo) ensures survival and proliferation of colony-forming unit erythroid (CFU-E) progenitor cells and their differentiation to hemoglobin-containing mature erythrocytes. A lack of … Epo-induced responses causes embryonic lethality, but mechanisms regulating the dynamic communication of cellular alterations to the organismal level remain unresolved. By time-resolved transcriptomics and proteomics, we show that Epo induces in CFU-E cells a gradual transition from proliferation signature proteins to proteins indicative for differentiation, including heme-synthesis enzymes. In the absence of the Epo receptor (EpoR) in embryos, we observe a lack of hemoglobin in CFU-E cells and massive iron overload of the fetal liver pointing to a miscommunication between liver and placenta. A reduction of iron-sulfur cluster-containing proteins involved in oxidative phosphorylation in these embryos leads to a metabolic shift toward glycolysis. This link connecting erythropoiesis with the regulation of iron homeostasis and metabolic reprogramming suggests that balancing these interactions is crucial for protection from iron intoxication and for survival.

Authors: S. Chakraborty, G. Andrieux, P. Kastl, L. Adlung, S. Altamura, M. E. Boehm, L. E. Schwarzmuller, Y. Abdullah, M. C. Wagner, B. Helm, H. J. Grone, W. D. Lehmann, M. Boerries, H. Busch, M. U. Muckenthaler, M. Schilling, U. Klingmuller

Date Published: 20th Sep 2022

Publication Type: Journal

Deciphering signal transduction networks in the liver by mechanistic mathematical modelling
LiSyM network, SMART-NAFLD

Abstract (Expand)

In health and disease, liver cells are continuously exposed to cytokines and growth factors. While individual signal transduction pathways induced by these factors were studied in great detail, the … cellular responses induced by repeated or combined stimulations are complex and less understood. Growth factor receptors on the cell surface of hepatocytes were shown to be regulated by receptor interactions, receptor trafficking and feedback regulation. Here, we exemplify how mechanistic mathematical modelling based on quantitative data can be employed to disentangle these interactions at the molecular level. Crucial is the analysis at a mechanistic level based on quantitative longitudinal data within a mathematical framework. In such multi-layered information, step-wise mathematical modelling using submodules is of advantage, which is fostered by sharing of standardized experimental data and mathematical models. Integration of signal transduction with metabolic regulation in the liver and mechanistic links to translational approaches promise to provide predictive tools for biology and personalized medicine.

Authors: Lorenza A. D’Alessandro, Ursula Klingmüller, Marcel Schilling

Date Published: 30th Jun 2022

Publication Type: Journal

Cell-to-cell variability in JAK2/STAT5 pathway components and cytoplasmic volumes defines survival threshold in erythroid progenitor cells.
LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF)

Abstract (Expand)

Survival or apoptosis is a binary decision in individual cells. However, at the cell-population level, a graded increase in survival of colony-forming unit-erythroid (CFU-E) cells is observed upon … stimulation with erythropoietin (Epo). To identify components of Janus kinase 2/signal transducer and activator of transcription 5 (JAK2/STAT5) signal transduction that contribute to the graded population response, we extended a cell-population-level model calibrated with experimental data to study the behavior in single cells. The single-cell model shows that the high cell-to-cell variability in nuclear phosphorylated STAT5 is caused by variability in the amount of Epo receptor (EpoR):JAK2 complexes and of SHP1, as well as the extent of nuclear import because of the large variance in the cytoplasmic volume of CFU-E cells. 24-118 pSTAT5 molecules in the nucleus for 120 min are sufficient to ensure cell survival. Thus, variability in membrane-associated processes is sufficient to convert a switch-like behavior at the single-cell level to a graded population-level response.

Authors: L. Adlung, P. Stapor, C. Tonsing, L. Schmiester, L. E. Schwarzmuller, L. Postawa, D. Wang, J. Timmer, U. Klingmuller, J. Hasenauer, M. Schilling

Date Published: 10th Aug 2021

Publication Type: Journal

Disentangling molecular mechanisms regulating sensitization of interferon alpha signal transduction.
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF)

Abstract (Expand)

Tightly interlinked feedback regulators control the dynamics of intracellular responses elicited by the activation of signal transduction pathways. Interferon alpha (IFNalpha) orchestrates antiviral … responses in hepatocytes, yet mechanisms that define pathway sensitization in response to prestimulation with different IFNalpha doses remained unresolved. We establish, based on quantitative measurements obtained for the hepatoma cell line Huh7.5, an ordinary differential equation model for IFNalpha signal transduction that comprises the feedback regulators STAT1, STAT2, IRF9, USP18, SOCS1, SOCS3, and IRF2. The model-based analysis shows that, mediated by the signaling proteins STAT2 and IRF9, prestimulation with a low IFNalpha dose hypersensitizes the pathway. In contrast, prestimulation with a high dose of IFNalpha leads to a dose-dependent desensitization, mediated by the negative regulators USP18 and SOCS1 that act at the receptor. The analysis of basal protein abundance in primary human hepatocytes reveals high heterogeneity in patient-specific amounts of STAT1, STAT2, IRF9, and USP18. The mathematical modeling approach shows that the basal amount of USP18 determines patient-specific pathway desensitization, while the abundance of STAT2 predicts the patient-specific IFNalpha signal response.

Authors: F. Kok, M. Rosenblatt, M. Teusel, T. Nizharadze, V. Goncalves Magalhaes, C. Dachert, T. Maiwald, A. Vlasov, M. Wasch, S. Tyufekchieva, K. Hoffmann, G. Damm, D. Seehofer, T. Boettler, M. Binder, J. Timmer, M. Schilling, U. Klingmuller

Date Published: 23rd Jul 2020

Publication Type: Journal

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Agenda for LiSyM-Cancer status seminar 2022
Forschungsnetzwerk LiSyM-Krebs, SMART-NAFLD, DEEP-HCC network, C-TIP-HCC network

Agenda for LiSyM-Cancer status seminar 2022

Creators: Olga Krebs, Susan Eckerle, Wolfgang Müller, Ursula Klingmüller, Ina Biermayer

Submitter: Olga Krebs

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Agenda Kickoff Meeting SMART-NAFLD
SMART-NAFLD

Agenda Kickoff Meeting SMART-NAFLD 1-2 december 2021 in Heidelberg

Creators: Ursula Klingmüller, Ina Biermayer

Submitter: Olga Krebs

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