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Trafficking and Signaling of Disease-Related Receptor Complexes

English title Trafficking and Signaling of Disease-Related Receptor Complexes
Applicant Berger Philipp
Number 146975
Funding scheme Project funding (Div. I-III)
Research institution Paul Scherrer Institut
Institution of higher education Paul Scherrer Institute - PSI
Main discipline Cellular Biology, Cytology
Start/End 01.04.2014 - 30.11.2017
Approved amount 343'960.00
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All Disciplines (4)

Discipline
Cellular Biology, Cytology
Pharmacology, Pharmacy
Molecular Biology
Biochemistry

Keywords (7)

GPCR; Rab GTPases; Receptor signaling; VEGFR2; Receptor trafficking; Angiogenesis; Receptor endocytosis

Lay Summary (German)

Lead
Unser Körper besteht aus vielen verschiedenen Zelltypen, die miteinander kommunizieren müssen. Die Zellen produzieren dazu Moleküle, die an Rezeptoren binden, die auf der Oberfläche von Zellen lokalisiert sind. Diese Rezeptoren vermitteln dann das Signal ins Innere der Zelle. Dieses Projekt studiert die Art und Weise der Signalübermittlung, insbesondere wo und wie Signale in der Zelle erzeugt werden. Dies ist wichtig, weil eine falsche Signalübermittlung Krankheiten wie z.B. Krebs oder Bluthochdruck auslösen kann.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Rezeptor Tyrosin Kinasen und G-protein gekoppelte Rezeptoren sind die beiden Haupttypen von membran-gebunden Rezeptoren an der Zelloberfäche. Als erstes untersuchen wir den Rezeptor für den vaskulären endothelialen Wachstumsfaktor (VEGFR-2, eine Rezeptor Tyrosin Kinase). Der VEGFR2 spielt ein wichtige Rolle bei der Bildung von Blutgefässen in unserem Körper. Allerdings ermöglicht er auch das Wachstum von Blutgefässen in Tumoren, was dazu führt, dass die Krebszellen besser mit Nährstoffen versorgt werden und der Tumor wachsen kann. Es gibt bereits Substanzen, die diese Signalübertragung blockieren und bei der Behandlung von Krebspatienten verwendet werden. Wir suchen neue Substanzen, die einen präziseren Eingriff in die Krebsentstehung und Ausbreitung erlauben.

Als zweites untersuchen wir die G-protein gekoppelte Rezeptoren für Serotonin, Dopamin und Glutamat (5-HT2A, D2DR und mGluR2). Diese Rezeptoren arbeiten zusammen und spielen eine wichtige Rolle bei der Entstehung von Schizophrenie. Ausserdem vermitteln sie die Eigenschaften von halluzinogenen Drogen. Wir untersuchen die Wechselwirkung dieser Rezeptoren und suchen nach neuen Wegen, wie ihre Signale moduliert werden können.

 

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Rezeptoren auf der Oberfläche von Zellen sind beliebte und validierte Ziele der pharmazeutischen Industrie, weil sie leicht zugänglich sind. Demzufolge aktivieren oder blockieren die meisten Medikamente, die auf dem Markt sind, solche Rezeptoren. Unser Projekt betreibt Grundlagenforschung in diesem Gebiet und soll neue Wege aufzeigen, wie man Krankheiten behandeln kann indem man das Verhalten dieser Rezeptoren verändert.

Direct link to Lay Summary Last update: 27.02.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Regulation of VEGFR2 trafficking and signaling by Rab GTPase-activating proteins
Xie Ye, Mansouri Maysam, Rizk Aurélien, Berger Philipp (2019), Regulation of VEGFR2 trafficking and signaling by Rab GTPase-activating proteins, in Scientific Reports, 9(1), 13342-13342.
Multigene delivery in mammalian cells: Recent advances and applications
Mansouri Maysam, Berger Philipp (2018), Multigene delivery in mammalian cells: Recent advances and applications, in Biotechnology Advances, 1.
Baculovirus-based genome editing in primary cells
Mansouri Maysam, Ehsaei Zahra, Taylor Verdon, Berger Philipp (2017), Baculovirus-based genome editing in primary cells, in Plasmid, 90, 5-9.
Highly efficient baculovirus-mediated multigene delivery in primary cells
Mansouri Maysam, Bellon-Echeverria Itxaso, Rizk Aurélien, Ehsaei Zahra, Cianciolo Cosentino Chiara, Silva Catarina S., Xie Ye, Boyce Frederick M., Davis M. Wayne, Neuhauss Stephan C. F., Taylor Verdon, Ballmer-Hofer Kurt, Berger Imre, Berger Philipp (2016), Highly efficient baculovirus-mediated multigene delivery in primary cells, in Nature Communications, 7, 11529-11529.
Strategies for multigene expression in eukaryotic cells.
Mansouri Maysam, Berger Philipp (2014), Strategies for multigene expression in eukaryotic cells., in Plasmid, 5, 12-1.

Collaboration

Group / person Country
Types of collaboration
Prof. Andreas Mayer, Universität Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
InterAx Biotech AG, Villigen Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
- Industry/business/other use-inspired collaboration
Prof. Dr. Imre Berger, University of Bristol Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. Mats Hellström, Uppsala University Sweden (Europe)
- 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
Gruppenseminar Novartis Individual talk Multigene delivery in mammalian cells to explore cellular functions 21.09.2017 Basel, Switzerland Berger Philipp;
Institutsseminar Kinderspital Zürich Individual talk Multigene delivery in mammalian cells to explore cellular functions 13.03.2017 Zürich, Switzerland Berger Philipp;
Institutsseminar Uni Bern Individual talk Multigene delivery in mammalian cells to explore cellular functions 31.10.2016 Bern, Switzerland Berger Philipp;
Institutsseminar Uni Basel Individual talk Multigene expression in mammalian cells and its application in cell biology 21.07.2016 Basel, Switzerland Berger Philipp;
Institutsseminar ETHZ Individual talk Multigene expression in mammalian cells and its application in cell biology 07.07.2016 Zürich, Switzerland Berger Philipp;
International Society for Stem Cell Research Poster Baculovirus-based multigene delivery to stem cells 15.06.2016 San Francisco, United States of America Berger Philipp; Xie Ye; Mansouri Maysam;
Institutsseminar Individual talk Multigene expression in mammalian cells and its application in cell biology 22.09.2015 Lausanne, Switzerland Berger Philipp;
Genome engineering: The CRISPR/Cas9 revolution Poster MultiPrime: a Baculovirus-based multigene expression system for mammalian cells’’ 15.09.2015 New York, United States of America Mansouri Maysam; Berger Philipp; Xie Ye;
Enable synthetic biology for mammalian cells Poster MultiPrime: A Baculovirus-based multigene expression system for mammalian cells 15.06.2015 Heidelberg, Germany Berger Philipp; Mansouri Maysam; Xie Ye;
LS2 meeting Poster MultiPrime: A Baculovirus-based multigene expression system for mammalian cells 15.01.2015 Zürich, Switzerland Berger Philipp; Mansouri Maysam; Xie Ye;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Tag der offenen Tür, Paul Scherrer Institut German-speaking Switzerland 2015

Awards

Title Year
Poster-Preis LS2 Meeting 2015 MultuPrime: A baculovirus-based multigene expression system for mammalian cells. 2015

Associated projects

Number Title Start Funding scheme
160805 Targeting Cancer Cells with Hybrid and Heterovalent Ligands at Controlled Distances 01.02.2016 Sinergia
132815 Linking G protein-coupled receptor structure to signaling output 01.12.2010 Project funding (Div. I-III)

Abstract

Receptor tyrosine kinases (RTKs) and G protein coupled receptors (GPCRs) are key components of cell physiology since they transmit signals from the outside to the cytoplasm of cells. Receptor tyrosine kinases possess a single transmembrane domain and are mainly involved in organism forming processes such as cell proliferation and differentiation. GPCRs are seven transmembrane domain receptors that modulate a wide variety of physiological processes including blood pressure, inflammation and mood. Both receptor families are consequently attractive targets for pharmaceutical companies. Ligand binding initiates signal transmission, internalization, and trafficking of the receptor. Recent studies have revealed that distinct isoforms of growth factors or some synthetic ligands activate only a part of the signaling pathways when compared with full agonists, and promote alternative trafficking routes within the cell, a process called biased signaling. Understanding this process is extremely important for drug development, since it could allow the optimization of the signaling outcome and drug response. In an ideal case, therapeutic effects associated with a particular signaling pathway could be separated from unwanted side effects caused by the activation of additional signaling pathways.The following topics will be addressed:A. New strategies to interfere with angiogenic signalingVEGF-A165a, one of the main drivers of tumor angiogenesis, leads to a different trafficking of VEGFR2 than does VEGF-A165b, which has only weak angiogenic potential. Interfering with VEGFR2 trafficking may therefore represent a new approach to prevent pathological angiogenesis in diseases such as cancer and macula degeneration.B. Trafficking of psychosis-related heterodimeric GPCR complexes.Hallucinogenic drugs act in vivo on the serotonin receptor type 2A (5-HT2A), which forms heterodimeric complexes with the metabotropic glutamate receptor 2 (mGluR2) or the dopamine receptor D2 (D2DR). We compare the influence of hallucinogenic and nonhallucinogenic drugs on receptor recycling and degradation, because the levels of these receptors are altered in schizophrenic patients. C. High resolution map of intracellular trafficking routesIntracellular receptor trafficking routes are currently not defined at high resolution. We will generate a high resolution map using Rab GTPases as markers.Scientific value: It becomes more and more evident that it is possible to identify ligands that activate only part of the signaling pathways of a particular receptor. These ligands are clinically extremely interesting. Most studies focus on the signalling output of the ligand / receptor complex, because the corresponding high-throughput technologies are established. We will focus on the dynamic distribution of receptors within cells, thereby creating novel complementary datasets for pharmacological intervention.
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