coNfirm

Networks of heart disease: Systems medicine approach to improve heart health


Cardiovascular disease is the leading cause of death in western industrial nations. In Germany, about 40 % of all deaths are caused by diseases of the cardiovascular system. Rising life expectancy is expected to increase the appearance of cardiovascular disease.

The alliance "coNfirm" is part of the networking fonds promoted to intensify the interdisciplinary interactions between the five modules of the research and support concept "e:Med - Establishing systems medicine in Germany". coNfirm is working with conditions of cardiovascular diseases such as heart failure, myocardial infarct and atrial fibrillation. The project aims to identify disease-spanning features and mechanisms using systems medicine approaches to gain profound knowledge of cardiovascular diseases. This is essential for the development of personalized medicine, including diagnostic, preventive and therapeutic measures.

The "coNfirm" network brings together nine e:Med groups, which are combining and evaluating different experimental datasets and clinical information obtained from project partners. To facilitate an efficient data exchange, datasets are harmonized and experimental standards as well as legal requirements are created. The developed tools for combining and exchanging big datasets can be transferred to many different areas to gain more insight in this field. This knowledge will be passed on to the e:Med community in workshops.

 

Subproject 1: Multi-species and multi-level data resource

Subproject 2: Bioinformatic approaches to generate common signaling pathways of cardiac diseases

Subproject 3: Methods of data exchange within coNfirm: rules, procedures and trust

Publications

Andrieux, G., Chakraborty, S., Das, T. and Boerries, M. (2020). "Alteration of Proteotranscriptomic Landscape Reveals the Transcriptional Regulatory Circuits Controlling Key-Signaling Pathways and Metabolic Reprogramming During Tumor Evolution." Front Cell Dev Biol 8. doi.org/10.3389/fcell.2020.586479.

Beyes, S., Andrieux, G., Schrempp, M., Aicher, D., Wenzel, J., Anton-Garcia, P., Boerries, M. and Hecht, A. (2019). "Genome-wide mapping of DNA-binding sites identifies stemness-related genes as directly repressed targets of SNAIL1 in colorectal cancer cells." Oncogene. www.ncbi.nlm.nih.gov/pubmed/31391555.

Chakraborty, S., Andrieux, G., Hasan, A. M. M., Ahmed, M., Hosen, M. I., Rahman, T., Hossain, M. A. and Boerries, M. (2019). "Harnessing the tissue and plasma lncRNA-peptidome to discover peptide-based cancer biomarkers." Scientific Reports 9(1): 12322. www.ncbi.nlm.nih.gov/pubmed/31444383.

Dicks, S., Jürgensen, L., Leuschner, F., Hassel, D., Andrieux, G. and Boerries, M. (2020). "Cardiac Regeneration and Tumor Growth—What Do They Have in Common?" Frontiers in Genetics 11. doi.org/10.3389/fgene.2020.586658.

Diofano, F., Weinmann, K., Schneider, I., Thiessen, K. D., Rottbauer, W. and Just, S. (2020). "Genetic compensation prevents myopathy and heart failure in an in vivo model of Bag3 deficiency." PLoS genetics 16(11): 24. www.ncbi.nlm.nih.gov/pubmed/33137814.

Dittman, J., Haydn, T., Metzger, P., Ward, G. A., Boerries, M., Vogler, M. and Fulda, S. (2020). "Next-generation hypomethylating agent SGI-110 primes acute myeloid leukemia cells to IAP antagonist by activating extrinsic and intrinsic apoptosis pathways." Cell Death Differ 27(6): 1878–1895. doi.org/10.1038/s41418-019-0465-8.

Frey, P., Devisme, A., Schrempp, M., Andrieux, G., Boerries, M. and Hecht, A. (2020). "Canonical BMP Signaling Executes Epithelial-Mesenchymal Transition Downstream of SNAIL1." J Cancers 12(4): 1019. doi.org/10.3390/cancers12041019.

Gross, A., Kracher, B., Kraus, J. M., Kuhlwein, S. D., Pfister, A. S., Wiese, S., Luckert, K., Potz, O., Joos, T., Van Daele, D., De Raedt, L., Kuhl, M. and Kestler, H. A. (2019). "Representing dynamic biological networks with multi-scale probabilistic models." Communications Biology 2: 21. www.ncbi.nlm.nih.gov/pubmed/30675519.

Hamarsheh, S. a., Osswald, L., Saller, B. S., Unger, S., De Feo, D., Vinnakota, J. M., Konantz, M., Uhl, F. M., Becker, H., Lübbert, M., Shoumariyeh, K., Schürch, C., Andrieux, G., Venhoff, N., Schmitt-Graeff, A., Duquesne, S., Pfeifer, D., Cooper, M. A., Lengerke, C., Boerries, M., Duyster, J., Niemeyer, C. M., Erlacher, M., Blazar, B. R., Becher, B., Groß, O., Brummer, T. and Zeiser, R. (2020). "Oncogenic KrasG12D causes myeloproliferation via NLRP3 inflammasome activation." Nature Communications 11(1659): 1–17. doi.org/10.1038/s41467-020-15497-1.

Hammoud, Z. and Kramer, F. (2020). "Multipath: An R Package to Generate Integrated Reproducible Pathway Models." Biology 9(12): 483. doi.org/10.3390/biology9120483.

Hawe, J. S., Theis, F. J. and Heinig, M. (2019). "Inferring Interaction Networks From Multi-Omics Data." Frontiers in Genetics 10: 535. www.ncbi.nlm.nih.gov/pubmed/31249591.

Heinig, M. (2018). "Using Gene Expression to Annotate Cardiovascular GWAS Loci." Front. Cardiovasc. Med 5. www.frontiersin.org/articles/10.3389/fcvm.2018.00059/full.

Hussung, S., Akhoundova, D., Hipp, J., Follo, M., Klar, R., Philipp, U., Scherer, F., von Bubnoff, N., Duyster, J., Börries, M., Wittel, U. and Fritsch, R. (2020). "Longitudinal Analysis of Cell-free Mutated KRAS and CA 19-9 Predicts Survival Following Curative Resection of Pancreatic Cancer." BMC cancer. doi.org/10.21203/rs.3.rs-60848/v1.

Hussung, S., Follo, M., Klar, R. F. U., Michalczyk, S., Fritsch, K., Nollmann, F., Hipp, J., Duyster, J., Scherer, F., von Bubnoff, N., Boerries, M., Wittel, U. and Fritsch, R. M. (2020). "Development and clinical validation of discriminatory multi-target digital droplet PCR assays for the detection of hot spot KRAS and NRAS mutations in cell-free DNA." The Journal of molecular diagnostics: JMD. doi.org/10.1016/j.jmoldx.2020.04.206.

Ikonomi, N., Kuehlwein, S. D., Schwab, J. D. and Kestler, H. A. (2020). "Awakening the HSC: Dynamic Modeling of HSC Maintenance Unravels Regulation of the TP53 Pathway and Quiescence." Frontiers in Physiology 11(848). doi.org/10.3389/fphys.2020.00848.

Ketterer, S., Mitschke, J., Ketscher, A., Schlimpert, M., Reichardt, W., Baeuerle, N., Hess, M. E., Metzger, P., Boerries, M., Peters, C., Kammerer, B., Brummer, T., Steinberg, F. and Reinheckel, T. (2020). "Cathepsin D deficiency in mammary epithelium transiently stalls breast cancer by interference with mTORC1 signaling." Nature Communications 11(5133): 1–18. doi.org/10.1038/s41467-020-18935-2.

Klett, H., Jürgensen, L., Most, P., Busch, M., Günther, F., Dobreva, G., Leuschner, F., Hassel, D., Busch, H. and Boerries, M. (2018). "Delineating the Dynamic Transcriptome Response of mRNA and microRNA during Zebrafish Heart Regeneration." Biomolecules 9(1). www.ncbi.nlm.nih.gov/pubmed/30597924.

Kozyra, E. J., Pastor, V. B., Lefkopoulos, S., Sahoo, S. S., Busch, H., Voss, R. K., Erlacher, M., Lebrecht, D., Szvetnik, E. A., Hirabayashi, S., Pasaulienė, R., Pedace, L., Tartaglia, M., Klemann, C., Metzger, P., Boerries, M., Catala, A., Hasle, H., de Haas, V., Kállay, K., Masetti, R., De Moerloose, B., Dworzak, M., Schmugge, M., Smith, O., Starý, J., Mejstrikova, E., Ussowicz, M., Morris, E., Singh, P., Collin, M., Derecka, M., Göhring, G., Flotho, C., Strahm, B., Locatelli, F., Niemeyer, C. M., Trompouki, E., Wlodarski, M. W. and Childhood, E. W. G. o. M. i. (2020). "Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency " Leukemia: 1–15. doi.org/10.1038/s41375-020-0899-5.

Lausser, L., Schäfer, L. M., Kühlwein, S. D., Kestler, A. M. R. and Kestler, H. A. (2020). "Detecting Ordinal Subcascades." Neural Processing Letters 52(3): 2583–2605. doi.org/10.1007/s11063-020-10362-0.

Lausser, L., Schafer, L. M., Schirra, L. R., Szekely, R., Schmid, F. and Kestler, H. A. (2019). "Assessing phenotype order in molecular data." Scientific Reports 9(1): 11746. www.ncbi.nlm.nih.gov/pubmed/31409831.

Lausser, L., Siegle, L., Rottbauer, W., Frank, D., Just, S. and Kestler, H. A. (2018). "Semantic Multi-Classifier Systems Identify Predictive Processes in Heart Failure Models across Species." Biomolecules 8(4). www.ncbi.nlm.nih.gov/pubmed/30486323.

Lausser, L., Szekely, R., Kessler, V., Schwenker, F. and Kestler, H. A. (2018). Selecting Features from Foreign Classes, Springer International Publishing.

Lausser, L., Szekely, R. and Kestler, H. A. (2020). "Chained correlations for feature selection." Advances in Data Analysis and Classification: 1–14. ideas.repec.org/a/spr/advdac/vyid10.1007_s11634-020-00397-5.html.

Lausser, L., Szekely, R., Klimmek, A., Schmid, F. and Kestler, H. A. (2020). "Constraining classifiers in molecular analysis: invariance and robustness." Journal of the Royal Society Interface 17(163): 14. www.ncbi.nlm.nih.gov/pubmed/32019472.

Maccari, M. E., Fuchs, S., Kury, P., Andrieux, G., Völkl, S., Bengsch, B., Lorenz, M. R., Heeg, M., Rohr, J., Jägle, S., Castro, C. N., Groß, M., Warthorst, U., König, C., Fuchs, I., Speckmann, C., Thalhammer, J., Kapp, F. G., Seidel, M. G., Dückers, G., Schönberger, S., Schütz, C., Führer, M., Kobbe, R., Holzinger, D., Klemann, C., Smisek, P., Owens, S., Horneff, G., Kolb, R., Naumann-Bartsch, N., Miano, M., Staniek, J., Rizzi, M., Kalina, T., Schneider, P., Erxleben, A., Backofen, R., Ekici, A., Niemeyer, C. M., Warnatz, K., Grimbacher, B., Eibel, H., Mackensen, A., Frei, A. P., Schwarz, K., Boerries, M., Ehl, S. and Rensing-Ehl, A. (2021). "A distinct CD38+CD45RA+ population of CD4+, CD8+, and double-negative T cells is controlled by FAS." J Exp Med 218(2). doi.org/10.1084/jem.20192191.

Marschner, D., Falk, M., Javorniczky, N. R., Hanke-Müller, K., Rawluk, J., Schmitt-Graeff, A., Simonetta, F., Haring, E., Dicks, S., Ku, M., Duquesne, S., Aumann, K., Rafei-Shamsabadi, D., Meiss, F., Marschner, P., Boerries, M., Negrin, R. S., Duyster, J., Zeiser, R. and Köhler, N. (2020). "MicroRNA-146a regulates immune-related adverse events caused by immune checkpoint inhibitors." JCI Insight 5(6). insight.jci.org/articles/view/132334.

Müller, A., Lausser, L., Wilhelm, A., Ropinski, T., Platzer, M., Neumann, H. and Kestler, H. A. (2020). "A perceptually optimised bivariate visualisation scheme for high-dimensional fold-change data." Advances in Data Analysis and Classification: 1–18. doi.org/10.1007/s11634-020-00416-5.

Norona, J., Apostolova, P., Schmidt, D., Ihlemann, R., Reischmann, N., Taylor, G., Köhler, N., de Heer, J., Heeg, S., Andrieux, G., Siranosian, B. A., Schmitt-Graeff, A., Pfeifer, D., Catalano, A., Frew, I., Proietti, M., Grimbacher, B., Bulashevska, A., Bhatt, A. S., Brummer, T., Clauditz, T. S., Zabelina, T., Kroeger, N., Blazar, B. R., Boerries, M., Ayuk, F. and Zeiser, R. (2020). "Glucagon like peptide-2 for Intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans." Blood. doi.org/10.1182/blood.2020005957.

Pott, A., Rottbauer, W. and Just, S. (2020). "Streamlining drug discovery assays for cardiovascular disease using zebrafish." Expert Opinion on Drug Discovery 15(1): 27-37. www.ncbi.nlm.nih.gov/pubmed/31570020.

Pott, A., Shahid, M., Köhler, D., Pylatiuk, C., Weinmann, K., Just, S. and Rottbauer, W. (2018). "Therapeutic Chemical Screen Identifies Phosphatase Inhibitors to Reconstitute PKB Phosphorylation and Cardiac Contractility in ILK-Deficient Zebrafish." Biomolecules 8(4). www.ncbi.nlm.nih.gov/pubmed/30463267.

R Mathew, N., Vinnakota, J. M., Apostolova, P., Erny, D., Hamarsheh, S. a., Andrieux, G., Kim, J.-S., Hanke, K., Goldmann, T., Chappell-Maor, L., El-Khawanky, N., Ihorst, G., Schmidt, D., Duyster, J., Finke, J., Blank, T., Boerries, M., Blazar, B. R., Jung, S., Prinz, M. and Zeiser, R. (2020). "Graft-versus-host disease of the CNS is mediated by TNF upregulation in microglia." The Journal of Clinical Investigation 130(3): 1315-1329. www.ncbi.nlm.nih.gov/pubmed/31846439.

Reischmann, N., Andrieux, G., Griffin, R., Reinheckel, T., Boerries, M. and Brummer, T. (2020). "BRAFV600E drives dedifferentiation in small intestinal and colonic organoids and cooperates with mutant p53 and Apc loss in transformation." Oncogene: 1–18. doi.org/10.1038/s41388-020-01414-9.

Sanchez-Gonzalez, I., Bobien, A., Molnar, C., Schmid, S., Strotbek, M., Boerries, M., Busch, H. and Olayioye, M. A. (2020). "miR-149 suppresses breast cancer metastasis by blocking paracrine interactions with macrophages." Cancer Res 80(6): 1330-1341. www.ncbi.nlm.nih.gov/pubmed/31911555.

Schumacher, D., Andrieux, G., Boehnke, K., Keil, M., Silvestri, A., Silvestrov, M., Keilholz, U., Haybaeck, J., Erdmann, G., Sachse, C., Templin, M., Hoffmann, J., Boerries, M., Schafer, R. and Regenbrecht, C. R. A. (2019). "Heterogeneous pathway activation and drug response modelled in colorectal-tumor-derived 3D cultures." PLoS Genet 15(3): e1008076. www.ncbi.nlm.nih.gov/pubmed/30925167.

Schwab, J. D. and Kestler, H. A. (2018). "Automatic Screening for Perturbations in Boolean Networks." Frontiers in Physiology 9: 431. www.ncbi.nlm.nih.gov/pubmed/29740342.

Schwab, J. D., Kühlwein, S. D., Ikonomi, N., Kühl, M. and Kestler, H. A. (2020). "Concepts in Boolean network modeling: What do they all mean?" Computational and Structural Biotechnology Journal. www.sciencedirect.com/science/article/pii/S200103701930460X.

Seifert, S., Gundlach, S., Junge, O. and Szymczak, S. (2020). "Integrating biological knowledge and gene expression data using pathway guided random forests: A benchmarking study." Bioinformatics. doi.org/10.1093/bioinformatics/btaa483.

Siegle, L., Schwab, J. D., Kühlwein, S. D., Lausser, L., Tümpel, S., Pfister, A. S., Kühl, M. and Kestler, H. A. (2018). "A Boolean network of the crosstalk between IGF and Wnt signaling in aging satellite cells." PLOS ONE 13(3): e0195126. www.ncbi.nlm.nih.gov/pubmed/29596489.

Thiam, P., Kestler, H. and Schwenker, F. (2020). Multimodal Deep Denoising Convolutional Autoencoders for Pain Intensity Classification based on Physiological Signals - ICPRAM 2020. ICPRAM 2020 - 9th International Conference on Pattern Recognition Applications and Methods, Proceedings of the 9th International Conference on Pattern Recognition Applications and Methods (ICPRAM 2020).

Thiam, P., Kestler, H. A. and Schwenker, F. (2020). "Two-Stream Attention Network for Pain Recognition from Video Sequences." SENSORS 20(3). doi.org/10.3390/s20030839.

Uhl, F. M., Chen, S., O’Sullivan, D., Edwards-Hicks, J., Richter, G., Haring, E., Andrieux, G., Halbach, S., Apostolova, P., Büscher, J., Duquesne, S., Melchinger, W., Sauer, B., Shoumariyeh, K., Schmitt-Graeff, A., Kreutz, M., Lübbert, M., Duyster, J., Brummer, T., Boerries, M., Madl, T., Blazar, B. R., Groß, O., Pearce, E. L. and Zeiser, R. (2020). "Metabolic reprogramming of donor T cells enhances graft-versus-leukemia effects in mice and humans." Science Translational Medicine 12(567): eabb8969. doi.org/10.1126/scitranslmed.abb8969.

Völkel, G., Laban, S., Fürstberger, A., Kühlwein, S. D., Ikonomi, N., Hoffman, T. K., Brunner, C., Neuberg, D. S., Gaidzik, V., Döhner, H., Kraus, J. M. and Kestler, H. A. (2020). "Analysis, identification and visualization of subgroups in genomics." Briefings Bioinf. doi.org/10.1093/bib/bbaa217.

Wenzel, J., Rose, K., Haghighi, E. B., Lamprecht, C., Rauen, G., Freihen, V., Kesselring, R., Boerries, M. and Hecht, A. (2020). "Loss of the nuclear Wnt pathway effector TCF7L2 promotes migration and invasion of human colorectal cancer cells." Oncogene: 1–17. doi.org/10.1038/s41388-020-1259-7.

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