Project Description

TP10: Identification of systems properties determining the dynamics of the hepatitis B virus infection cycle and cross-talk to host cell responses

The dynamics of the cross-talk of the HBV infection cycle with host cell responses is studied by quantitative mass spectrometry. Based on this data a mathematical model of the HBV infection cycle is calibrated and will be linked to a dynamic pathway model of interferon (IFN)α induced antiviral responses. The aim is to identify mechanisms responsible for the synergistic effects of Myrcludex B (MyrB) and pegylated IFNα (PEG-IFNα) that was observed in clinical trials and thereby provide means to identify patients that might particularly benefit from the co-treatment of MyrB and PEG-IFNα.
D’Alessandro LA, Klingmüller U, Schilling M. (2022) Deciphering signal transduction networks in the liver by mechanistic mathematical modelling. Biochem J. 479 (12): 1361–1374. doi:

Robichon K, Maiwald T, Schilling M, Schneider A, Willemsen J, Salopiata F, Teusel M, Kreutz C, Ehlting C, Huang J, Chakraborty S, Huang X, Damm G, Seehofer D, Lang PA, Bode JG, Binder M, Bartenschlager R, Timmer J, Klingmüller U. Identification of Interleukin1β as an Amplifier of Interferon alpha-induced Antiviral Responses. PLoS Pathog. 2020 Oct 1;16(10):e1008461. doi: 10.1371/journal.ppat.1008461. (TP09, TP10, TP11)

Lampl S, Janas MK, Donakonda S, Brugger M, Lohr K, Schneider A, Manske K, Sperl LE, Kläger S, Küster B, Wettmarshausen J, Müller C, Laschinger M, Hartmann D, Hüser N, Perocchi F, Schmitt-Kopplin P, Hagn F, Zender L, Hornung V, Borner C, Pichlmair A, Kashkar H, Klingenspor M, Prinz M, Schreiner S, Conrad M, Jost PJ, Zischka H, Steiger K, Krönke M, Zehn D, Protzer U, Heikenwälder M, Knolle PA, Wohlleber D. Reduced mitochondrial resilience enables non-canonical induction of apoptosis after TNF receptor signaling in virus-infected hepatocytes. J Hepatol. 2020 Jun 26:S0168-8278(20)30398-6. doi: 10.1016/j.jhep.2020.06.026. (TP05, TP06, TP10, TP11, TP13, TP16, TP18)

Kok F, Rosenblatt M, Teusel M, Nizharadze T, Gonçalves Magalhães V, Dächert C, Maiwald T, Vlasov A, Wäsch M, Tyufekchieva S, Hoffmann K, Damm G, Seehofer D, Boettler T, Binder M, Timmer J, Schilling M, Klingmüller U. 2020. Disentangling molecular mechanisms regulating sensitization of interferon alpha signal transduction. Molecular Systems Biology 2020 Jul;16(7):e8955. doi: 10.15252/msb.20198955. (TP10)

Hass H, Loos C, Alvarez ER, Timmer J, Hasenauer J, Kreutz C. 2019. Benchmark Problems for Dynamic Modeling of Intracellular Processes. Bioinformatics. Bioinformatics 35: 3073-3082.
Kaschek D, Mader W, Fehling-Kaschek M, Rosenblatt M, Timmer J. 2019. Dynamic Modeling, Parame-ter Estimation, and Uncertainty Analysis in R. Journal of Statistical Software. 10: 1-32.
Lucarelli P, Schilling M, Kreutz C, Vlasov A, Boehm ME, Iwamoto N, Steiert B, Lattermann S, Wäsch M, Stepath M, Matter MS, Heikenwälder M, Hoffmann K, Deharde D, Damm G, Seehofer D, Muciek M, Gretz N, Lehmann WD, Timmer J, Klingmüller U. 2018. Resolving the Combinatorial Complexity of Smad Protein Complex Formation and Its Link to Gene Expression. Cell Syst. 6(1):75-89.
Oppelt A, Kaschek D, Huppelschoten S, Sison-Young R, Zhang F, Buck-Wiese M, Herrmann F, Malkusch S, Krüger CL, Meub M, Merkt B, Zimmermann L, Schofield A, Jones RP, Malik H, Schilling M, Heilemann M, van de Water B, Goldring CE, Park BK, Timmer J, Klingmüller U. 2018. Model-based identification of TNFα-induced IKKβ-mediated and IκBα-mediated regulation of NFκB signal transduc-tion as a tool to quantify the impact of drug-induced liver injury compounds. NPJ Syst Biol Appl. 4:23.
Sobotta S, Raue A, Huang X, Vanlier J, Jünger A, Bohl S, Albrecht U, Hahnel MJ, Wolf S, Mueller NS, D'Alessandro LA, Mueller-Bohl S, Boehm ME, Lucarelli P, Bonefas S, Damm G, Seehofer D, Lehmann WD, Rose-John S, van der Hoeven F, Gretz N, Theis FJ, Ehlting C, Bode JG, Timmer J, Schilling M, Klingmüller U. 2017. Model Based Targeting of IL-6-Induced Inflammatory Responses in Cultured Pri-mary Hepatocytes to Improve Application of the JAK Inhibitor Ruxolitinib. Front Physiol. 8:775
Rosenblatt M, Timmer J, Kaschek D. 2016. Customized Steady-State Constraints for Parameter Esti-mation in Non-Linear Ordinary Differential Equation Models. Front Cell Dev Biol. 4:41.
Maiwald T, Hass H, Steiert B, Vanlier J, Engesser R, Raue A, Kipkeew F, Bock HH, Kaschek D, Kreutz C, Timmer J. 2016. Driving the Model to Its Limit: Profile Likelihood Based Model Reduction. PLoS One. 11(9):e0162366.
D'Alessandro LA, Samaga R, Maiwald T, Rho SH, Bonefas S, Raue A, Iwamoto N, Kienast A, Waldow K, Meyer R, Schilling M, Timmer J, Klamt S, Klingmüller U. 2015. Disentangling the Complexity of HGF Signaling by Combining Qualitative and Quantitative Modeling. PLoS Comput Biol. 11(4):e1004192.
Mueller S, Huard J, Waldow K, Huang X, D'Alessandro LA, Bohl S, Börner K, Grimm D, Klamt S, Klingmüller U, Schilling M. 2015. T160-phosphorylated CDK2 defines threshold for HGF dependent proliferation in primary hepatocytes. Mol Syst Biol. 11(3):795.
Raue A, Steiert B, Schelker M, Kreutz C, Maiwald T, Hass H, Vanlier J, Tönsing C, Adlung L, Engesser R, Mader W, Heinemann T, Hasenauer J, Schilling M, Höfer T, Klipp E, Theis F, Klingmüller U, Schö-berl B, Timmer J. 2015. Data2Dynamics: a modeling environment tailored to parameter estimation in dynamical systems. Bioinformatics. 31(21):3558-60.