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Mechanobiology of Extracellular Matrix

English title Mechanobiology of Extracellular Matrix
Applicant Vogel Viola
Number 175839
Funding scheme Project funding (Div. I-III)
Research institution Angewandte Mechanobiologie Gesundheitswissenschaften und Technologie ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Biophysics
Start/End 01.10.2017 - 30.09.2021
Approved amount 800'000.00
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All Disciplines (2)

Discipline
Biophysics
Other disciplines of Engineering Sciences

Keywords (5)

Mechanobiology; Extracellular Matrix; Peptide probes; Molecular Bioengineering; Fibrosis

Lay Summary (German)

Lead
Das neue Gebiet der Mechanobiologie benutzt Nanotechnologien um Mechanismen zu identifizieren, wie externe und intern-generierte Kräfte Zellfunktionen regulieren können. Wir untersuchen hier, wie Zellkräfte den Aufbau und pathologische Transformationen von extrazellulärer Matrix steuern, und dies rückkoppelnd Zell- und Gewebefunktionen verändert.
Lay summary
Viele progressive Erkrankungen, wie Krebs oder Fibrosen, gehen einher mit einem strukturellen Umbau der extrazellulären Matrix. Aber, wie die Rückkopplung zwischen extrazellulärer Matrix und Zellen (und umgekehrt) diese Transformationen antreibt, ist bisher unbekannt. Dieses Unwissen ist zumindest teilweise auf das Fehlen von Sonden zurückzuführen, um entweder Zellzugkräfte in lebenden Geweben oder die mechanische Belastung von Matrixfasern zu messen. Um neuartige diagnostische und therapeutische Therapien für diese oft unheilbaren Erkrankungen zu entwickeln, muss ein fundiertes Verständnis der Mechanobiologie von extrazellulärer Matrix entwickelt werden. Mit Hilfe von unseren neu entwickelten Peptidproben, möchten wir im Rahmen dieses Forschungsprojektes verstehen, wie die gegenseitige Rückkopplung zwischen Kräften, Gewebemechanik und mechanisch-chemischer Umschaltung der Proteinfunktionen (wie sie durch Streckung induziert werden) das Gewebewachstum, sowie Heilungsprozesses aber auch pathologische Veränderung des Bindegewebes steuert. In diesem multidisziplinären Projekt werden wir histologische Gewebeschnitte von gesunden und erkrankten Organen analysieren, als auch mit im Labor gezüchteten Mikrogeweben arbeiten. Ziel ist es Faktoren zu identifizieren, die die pathologischen Transformationen der extrazellulären Matrix antreiben und diese Erkenntnisse langfristig medizinisch zu nutzen
Direct link to Lay Summary Last update: 12.10.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
Tissue transglutaminase in fibrosis — more than an extracellular matrix cross-linker
Benn Mario C., Weber Willi, Klotzsch Enrico, Vogel Viola, Pot Simon A. (2019), Tissue transglutaminase in fibrosis — more than an extracellular matrix cross-linker, in Current Opinion in Biomedical Engineering, 10, 156-164.
Tensile forces drive a reversible fibroblast-to-myofibroblast transition during tissue growth in engineered clefts
Kollmannsberger Philip, Bidan Cécile M., Dunlop John W. C., Fratzl Peter, Vogel Viola (2018), Tensile forces drive a reversible fibroblast-to-myofibroblast transition during tissue growth in engineered clefts, in Science Advances, 4(1), eaao4881-eaao4881.

Collaboration

Group / person Country
Types of collaboration
PSI Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Institute of Neuropathology, University Hospital Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Universität Würzburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
INSERM U1109 - Strasbourg France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
UZH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Keio University (Keio Gijuku Daigaku) - Tokyo Japan (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
8th International Conference on Mechanics of Biomaterials and Tissues Talk given at a conference Keynote: Mechanobiology: from single cells to tissues 17.12.2019 Hawaii, United States of America Vogel Viola;
Goodbye Flat Biology: Advancing 3D‐based Models for Cancer Biology and Drug Discovery Talk given at a conference Unraveling the mechanobiology of extracellular matrix and of macrophages 11.11.2019 Berlin, Germany Vogel Viola;
Nano-Bio-Physics Symposium 2019, Festsymposium Hermann Gaub Talk given at a conference Mechanobiology at the single molecule level 07.09.2019 München, Germany Vogel Viola;
Swiss Society for Biomedical Engineering (SSBE) Talk given at a conference Keynote: Nanotech mechanosensors with forceful medical implications 27.08.2019 Geneva, Switzerland Vogel Viola;
TUM Physik-Kolloquium Talk given at a conference Proteins as mechano-chemical nanoswitches: from atomistic simulations to medical applications 10.07.2019 München, Germany Vogel Viola;
IONS Intern. OSA Network of Students Talk given at a conference Plenary: Mechanobiology: a forceful player in health and disease 28.06.2019 Barcelona, Spain Vogel Viola;
ISACB + ISVTE 2019 Combined Inter. Symposium for Applied Cardiovascular Biology and Vascular Tissue Engineering Talk given at a conference Mechanobiology: a forceful player in health and disease 20.06.2019 Zürich, Switzerland Vogel Viola;
Einweihung Nano-Institut München Talk given at a conference Nano-Schalter mit kraftvollen biologischen Konsequenzen 17.06.2019 München, Germany Vogel Viola;
Nature conference on Engineering Biology for Medicine Talk given at a conference Nanosensors Engineered for Mechanobiology Applications 20.05.2019 Durham, United States of America Vogel Viola;
GRC Conference, Fibronectin, Integrins and Related Molecules Talk given at a conference Mechanobiology of extracellular matrix in healthy and diseased tissues 09.05.2019 Barga Lucca, Italy Vogel Viola;
Kongress der Deutschen Gesellschaft für Biomechanik Talk given at a conference Keynote: Mechanobiology: a forceful player in health and disease 04.04.2019 Berlin, Germany Vogel Viola;
RegMed Forum 2018 Talk given at a conference Keynote: Inspired by bacteria: clever nanosensors to measure tissue fiber tension 18.10.2018 Berlin, Germany Vogel Viola;
Einstein in the Dom, Einstein Stiftung Talk given at a conference Dem molekularen Lego auf der Spur 17.10.2018 Berlin, Germany Vogel Viola;
9th Symposium "Physics of Cancer" Talk given at a conference Distinguished: New peptide probes to map the tensional states of ECM fibers in tumour tissues 25.09.2018 Leipzig, Germany Vogel Viola;
29th European Conference on Biomaterials Talk given at a conference Plenary: Mechanobiology: a rapidly growing field with forceful implications 11.09.2018 Maastricht, Netherlands Antilles Vogel Viola;
CLINAM 2018 Talk given at a conference Bacterial Nanoglues Targeting Wound Sites for Theranostic Applications to Read out Tissue Fiber Tensions in Health and Disease 03.09.2018 Basel, Switzerland Vogel Viola;
BIOINTERFACES INTERNATIONAL CONFERENCE Talk given at a conference Keynote: Unraveling the crosstalk between tissue tension and tissue functions 16.08.2018 Zürich, Switzerland Vogel Viola;
Seminar at the Kennedy Institute Talk given at a conference How does the Mechanobiology of extracellular Matrix steer cancer progression? 25.07.2018 Oxford, Great Britain and Northern Ireland Vogel Viola;
RCSI Molecular & Cellular Therapeutics (MCT) Royal College of Surgeons in Ireland Talk given at a conference How does the Mechanobiology of extracellular Matrix steer cancer progression? 16.07.2018 Dublin, Ireland Vogel Viola;
8th World Congress of Biomechanics Talk given at a conference De novo grown 3D microtissues to investigate factors that drive the fibroblast-to-myofibroblast transition and can reverse it 12.07.2018 Dublin, Ireland Benn Mario Christian;
8th World Congress in Biomechanics Talk given at a conference Keynote: Assessing the Tensional State of Fibronectin Fibers at the Organ Level: Healthy Tissues versus Tumor Stroma 08.07.2018 Dublin, Iran Vogel Viola;
Forces in cancer: interdisciplinary approaches in tumour mechanobiology Talk given at a conference Assessing the tensional state of fibronectin fibres in cancer stroma 19.06.2018 London, Great Britain and Northern Ireland Vogel Viola;
Young Researchers in Life Sciences 2018, Paris Talk given at a conference Medical Technologies Inspired by Bacteria 04.05.2018 Paris, France Vogel Viola;
Nerem Lecture: 2018 Regenerative Medicine Workshop, Synergizing Science, Engineering, and Clinical Translation Talk given at a conference Nerem Lecture “Unravelling the secrets of how the Mechanobiology of Extracellular Matrix Regulates Cell and Tissue Functions” 21.03.2018 Charleston, United States of America Vogel Viola;
Multiscale Mechanochemistry & Mechanobiology from Molecular mechanisms to smart Materials Talk given at a conference Mechanobiology of Extracellular Matrix: from cells to organs 18.10.2017 Berlin, Germany Vogel Viola;


Associated projects

Number Title Start Funding scheme
183525 From Cells to Tissues: A lattice light sheet microscope to improve spatiotemporal resolution 01.10.2019 R'EQUIP
156931 Mechanotransduction processes, from the cell periphery to the nucleus, in 2D versus 3D microenvironments 01.10.2014 Interdisciplinary projects
170112 Acronym: Angio-Fib - How pericellular matrix orchestrates the angiogenic-to-fibrotic transition 01.11.2016 Project funding (Div. I-III)

Abstract

Major extracellular matrix (ECM) remodeling accompanies disease progression of many organs, including cancer, yet how the feedback between ECM and cells (and vice versa) drives these transformations remains unknown. This is at least in part due to the lack of probes to either measure cell traction forces in living tissues or the mechanical strain of ECM fibers. Since no technique exists today to diagnose early fibrotic tissue transformations, introducing new nanoscale sensors that can probe the tensional state of ECM fibers (i.e. their strain), once validated, opens the door for exploitation of the most promising candidates as diagnostic or therapeutic tools. The ECM protein fibronectin (FN) is at the center stage directing early development, wound healing, but also during pathological tissue transformations in fibrosis and cancer. Our aim is to learn how the tensile state of ECM fibrils controls cells and tissue functions, how this is altered during disease and whether or not this drives disease progression. Our recent discovery of reliable peptide probes that can visualize and distinguish for the first time between relaxed and stretched FN fibers in histological tissues sections defines a major step forward to achieving this goals. After this breakthrough, the goal of this proposal is to first clarify whether the occurrence of relaxed versus total FN fibers plays a significant role in regulating tissue homeostasis versus pathological states of the ECM (Aim 1). We will thereby mostly focus on biomarkers known to drive fibrosis and tumor progression. Next and since nothing is known how the tensile state of FN fibers relates to the upregulation of these biomarkers, we will develop a mechanistic understanding using in vitro 3D microtissues (Aim 2). Their bottom-up assembly will allow us to control and fine-tune the multifaceted parameters known to be involved in disturbing the equilibrium in tissue homeostasis towards pathological disorders of the ECM. Based on the outcome of the studies in Aims 1&2, we plan to further confirm our derived hypothesis using mouse models and conduct pharmaceutical inhibitor. Depending on the outcomes of the studies in Aims 1&2, we will go back to mouse models to test derived hypotheses with the help of pharmaceutical inhibitors of essential tension-regulated signaling pathways (Aim 3). Our long-term goal is to utilize the knowledge gained to develop novel diagnostic and therapeutic therapies to address diseases such as fibrosis and cancer, however to get into the clinic, we first need to lay the basic science foundations that are essential for their translation as proposed here. Filling this knowledge gap will impact many disciplines, from cell biology to medicine and the pharma industry. The impact of the proposed study thus goes far beyond the mapping of the tensional states of FN fibers. Our peptides are promising candidates as diagnostic tools or to deliver therapeutic payloads, particularly as fibrotic diseases are progressive and ultimately lead to the loss of vital organ functions, early diagnosis is essential to intervene early. These experiments will also allow us to assess the predictive value of our microtissue platforms by mimicking disease outcomes using a well-defined set of tunable parameters, including inhibitors to tune signaling pathways that are likely involved in sensing the tensional state of FN fibers and the downstream nuclear transcription factors and target genes. If good correlations between microtissue and organ sections can be found, this has far reaching consequences as they can then be utilized in general as well-controlled 3D in vitro test screening platforms for drugs.Taken together, investing into the development of new technologies will not only allow major new insights into the mechano-regulation of ECM, but is also important in Medicine.
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