title: Towards a Pathway Inventory of the Human Brain for Modeling Disease Mechanisms Underlying Neurodegeneration.
abstract: Molecular signaling pathways have been long used to demonstrate interactions among upstream causal molecules and downstream biological effects. They show the signal flow between cell compartments, the majority of which are represented as cartoons. These are often drawn manually by scanning through the literature, which is time-consuming, static, and non-interoperable. Moreover, these pathways are often devoid of context (condition and tissue) and biased toward certain disease conditions. Mining the scientific literature creates new possibilities to retrieve pathway information at higher contextual resolution and specificity. To address this challenge, we have created a pathway terminology system by combining signaling pathways and biological events to ensure a broad coverage of the entire pathway knowledge domain. This terminology was applied to mining biomedical papers and patents about neurodegenerative diseases with focus on Alzheimer's disease. We demonstrate the power of our approach by mapping literature-derived signaling pathways onto their corresponding anatomical regions in the human brain under healthy and Alzheimer's disease states. We demonstrate how this knowledge resource can be used to identify a putative mechanism explaining the mode-of-action of the approved drug Rasagiline, and show how this resource can be used for fingerprinting patents to support the discovery of pathway knowledge for Alzheimer's disease. Finally, we propose that based on next-generation cause-and-effect pathway models, a dedicated inventory of computer-processable pathway models specific to neurodegenerative diseases can be established, which hopefully accelerates context-specific enrichment analysis of experimental data with higher resolution and richer annotations.
authors.affiliation: Department of Bioinformatics, Fraunhofer Institute for Algorithms and Scientific Computing (SCAI), Schloss Birlinghoven, Sankt Augustin, Germany.|Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn-Aachen International Center for Information Technology, Bonn, Germany.
authors.forename: Anandhi
authors.initials: A
authors.lastname: Iyappan
authors.affiliation: Department of Bioinformatics, Fraunhofer Institute for Algorithms and Scientific Computing (SCAI), Schloss Birlinghoven, Sankt Augustin, Germany.|Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn-Aachen International Center for Information Technology, Bonn, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Gündel
authors.affiliation: Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shahid
authors.affiliation: University of Luxembourg, Faculty of Science, Technology and Communication, Life Sciences Research Unit, Luxembourg-Limpertsberg, Luxembourg.
authors.forename: Jiali
authors.initials: J
authors.lastname: Wang
authors.affiliation: No affiliation.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Bioinformatics, Fraunhofer Institute for Algorithms and Scientific Computing (SCAI), Schloss Birlinghoven, Sankt Augustin, Germany.
authors.forename: Heinz-Theodor
authors.initials: HT
authors.lastname: Mevissen
authors.affiliation: ZBMED Leibniz Information Centre for Life Sciences, Cologne, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Müller
authors.affiliation: Department of Bioinformatics, Fraunhofer Institute for Algorithms and Scientific Computing (SCAI), Schloss Birlinghoven, Sankt Augustin, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Fluck
authors.affiliation: Aix-Marseille Université, Institut de Neurosciences des Systèmes, Faculté de Médecine, Marseille, France.
authors.forename: Viktor
authors.initials: V
authors.lastname: Jirsa
authors.affiliation: Codemart, Str. Petofi Sandor, Cluj Napoca, Romania.
authors.forename: Lia
authors.initials: L
authors.lastname: Domide
authors.affiliation: Department of Bioinformatics, Fraunhofer Institute for Algorithms and Scientific Computing (SCAI), Schloss Birlinghoven, Sankt Augustin, Germany.|Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn-Aachen International Center for Information Technology, Bonn, Germany.
authors.forename: Erfan
authors.initials: E
authors.lastname: Younesi
authors.affiliation: Department of Bioinformatics, Fraunhofer Institute for Algorithms and Scientific Computing (SCAI), Schloss Birlinghoven, Sankt Augustin, Germany.|Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn-Aachen International Center for Information Technology, Bonn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hofmann-Apitius
mesh_terms: D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D016208:Databases, Factual; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000502:physiology; D008959:Models, Neurological; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology*; D009626:Terminology as Topic
keywords: Alzheimer’s disease; disease mechanism; disease modeling; neurodegeneration; pathway terminology