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The Role of microRNAs in Immune Regulation

English title The Role of microRNAs in Immune Regulation
Applicant Jeker Lukas
Number 144860
Funding scheme SNSF Professorships
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Immunology, Immunopathology
Start/End 01.03.2014 - 28.02.2018
Approved amount 1'620'973.00
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Keywords (12)

immune regulation; regulatory T cells; microRNA; miR-17-92; T follicular helper cell; preclinical animal models; non-coding RNA; in vivo genetics; posttranscriptional gene regulation; experimental autoimmune encephalitis; autoimmune disease; T cell tolerance

Lay Summary (German)

Lead
Das menschliche Immunsystem (Abwehrsystem) besteht aus vielen Milliarden weisser Blutkörperchen. Einen Teil davon nennen wir T Zellen. Mangelhafte Zahl oder Funktion von T Zellen führt zu Immunschwäche. Im Gegensatz dazu steht eine Ueberfunktion der T Zellen, die zu schweren Erkrankungen führen können. Multiple Sklerose (Gehirn) und Typ 1 Diabetes (Bauchspeicheldrüse) sind Beispiele solcher sogenannter Autoimmunkrankheiten (AI-KH). Leider sind die bisherigen Behandlungsmöglichkeiten beschränkt und haben oft schwere Nebenwirkungen.
Lay summary

Ziele:

Wir untersuchen zwei wichtige spezialisierte T Zell Subtypen, die bei Autoimmunkrankheiten eine Rolle spielen. Im Speziellen möchten wir mehr über kurze RNA Moleküle (microRNAs) lernen, die andere Gene hemmen und so zu deren Regulation beitragen. Bisher ist sehr wenig über die Funktion von microRNAs im Immunsystem bekannt. Wir werden eine detaillierte Analyse vornehmen, welche Funktionen microRNAs in beiden Zelltypen spielen und welche genetische Netzwerke von bestimmten microRNAs reguliert werden. Hierzu verwenden wir Techniken, die in den letzten Jahren entwickelt wurden und bis vor wenigen Jahren unvorstellbar waren.

 

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojektes:

Unsere Forschungsresultate werden zu einem besseren Verständnis des Immunsystems führen und könnten eine Grundlage für neue Ansätze für Therapien von Autoimmunkrankheiten bieten. Zudem könnten unsere Resultate für die Entwicklung von Tests für eine verbesserte Erkennung von Autoimmunkrankheiten oder der Ueberwachung von Behandlungserfolgen wichtig sein. Unsere Grundlagenerkenntnisse werden von anderen  Wissenschaftlern an Universitäten sowie von der pharmazeutischen Industrie weiter verfolgt werden.

 

Direct link to Lay Summary Last update: 07.02.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
miR-15/16 Restrain Memory T Cell Differentiation, Cell Cycle, and Survival
Gagnon John D., Kageyama Robin, Shehata Hesham M., Fassett Marlys S., Mar Darryl J., Wigton Eric J., Johansson Kristina, Litterman Adam J., Odorizzi Pamela, Simeonov Dimitre, Laidlaw Brian J., Panduro Marisella, Patel Sana, Jeker Lukas T., Feeney Margaret E., McManus Michael T., Marson Alexander, Matloubian Mehrdad, Sanjabi Shomyseh, Ansel K. Mark (2019), miR-15/16 Restrain Memory T Cell Differentiation, Cell Cycle, and Survival, in Cell Reports, 28(8), 2169-2181.e4.
MicroRNAs 24 and 27 Suppress Allergic Inflammation and Target a Network of Regulators of T Helper 2 Cell-Associated Cytokine Production
Pua Heather H., Steiner David F., Patel Sana, Gonzalez Jeanmarie R., Ortiz-Carpena Jorge F., Kageyama Robin, Chiou Ni-Ting, Gallman Antonia, de Kouchkovsky Dimitri, Jeker Lukas T., McManus Michael T., Erle David J., Ansel K. Mark (2016), MicroRNAs 24 and 27 Suppress Allergic Inflammation and Target a Network of Regulators of T Helper 2 Cell-Associated Cytokine Production, in Immunity, 44(4), 821-832.
Identification of MiR-205 As a MicroRNA That Is Highly Expressed in Medullary Thymic Epithelial Cells
Khan Imran S., Park Chong Y., Mavropoulos Anastasia, Shariat Nikki, Pollack Joshua L., Barczak Andrea J., Erle David J., McManus Michael T., Anderson Mark S., Jeker Lukas T. (2015), Identification of MiR-205 As a MicroRNA That Is Highly Expressed in Medullary Thymic Epithelial Cells, in PLOS ONE, 10(8), e0135440-e0135440.
Targeting microRNAs for immunomodulation
Jeker Lukas T, Marone Romina (2015), Targeting microRNAs for immunomodulation, in Current Opinion in Pharmacology, 23, 25-31.
Canonical microRNAs in thymic epithelial cells promote central toleranceCellular immune response
Khan Imran S., Taniguchi Ruth T., Fasano Kayla J., Anderson Mark S., Jeker Lukas T. (2014), Canonical microRNAs in thymic epithelial cells promote central toleranceCellular immune response, in European Journal of Immunology, 44(5), 1313-1319.

Collaboration

Group / person Country
Types of collaboration
Prof. Anna Fontcuberta, EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Prof. M. Ansel United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Ed Palmer Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Christoph Gerber Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Industry/business/other use-inspired collaboration
Prof. Onur Boyman Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Mihaela Zavolan Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Christoph Hess Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Gennaro de Libero Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Xuyu Zhou, Chinese Academy of Science, Beijing China (Asia)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Pawel Pelczar Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dirk Baumjohann Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Daniel Pinschewer Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Alfred Zippelius Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Invited Plenary Lecture - 28th Challenge in Virology Talk given at a conference Genome Engineering for Immunologic Reprogramming - First Results 19.01.2018 Grindelwald, Switzerland Jeker Lukas;
Invited seminar speaker - Ludwig-Maximilians-University Individual talk Genome engineering in primary T cells 18.05.2017 Munich, Germany Jeker Lukas;
Invited Seminar Speaker - Medizinische Hochschule Hannover Individual talk Genome engineering in primary T cells 26.04.2017 Hannover, Germany Jeker Lukas;
Invited Seminar Speaker - Institute of Molecular Genetics of the Czechoslovak Academy of Sciences Individual talk Genome engineering in primary T cells 15.03.2017 Prague, Czech Republic Jeker Lukas;
Keystone Meeting on Precision Genome Engineering Poster Multiplexed gene editing enriches gene-corrected scurfy T cells with restored Foxp3 expression 08.01.2017 Breckenridge, CO, United States of America Jeker Lukas;
Gordon Research Conference on Immunochemistry & Immunobiology Poster Highly efficient multiplexed homology directed repair in primary T cells 19.06.2016 Lucca, Italy Jeker Lukas;
Invited seminar speaker - Babraham Institute Individual talk microRNAs controlling T cells - Are we ready for the next step? 25.04.2016 Cambridge, Great Britain and Northern Ireland Jeker Lukas;
Student retreat of the Institute for Research in Biomedicine, Bellinzona, Switzerland Talk given at a conference T cell Biology - microRNAs add spice to the menue 06.04.2016 Engelberg, Switzerland Jeker Lukas;
World Immune Regulation Meeting Poster A simple System to Achieve High Efficiency Genome Editing in Primary T Cells 16.03.2016 Davos, Switzerland Jeker Lukas;
Cutting Edge Topics: Seminars in Immunology & Infection Biology, Institute of Experimental Immunology, University of Zurich and ETH Zurich Individual talk T Cell Biology - microRNAs add Spice to the Menue 08.03.2016 Zurich, Switzerland Jeker Lukas;
DBM Research Day Talk given at a conference Understanding How T Cells Regulate the Immune Response: microRNAs add Spice to the Menue 21.01.2016 Basel, Switzerland Jeker Lukas;
Meeting on Regulatory T cells Talk given at a conference microRNAs and Immune Regulation: New Tools Wanted! 22.10.2015 Leuven, Belgium Gorka Oliver; Jeker Lukas;
Molecular Pathology Seminar Series - Johns Hopkins University, MD, USA Individual talk microRNAs and Immune Regulation 01.04.2015 Baltimore, United States of America Jeker Lukas;
Department of Microbiology and Immunology - Infection and Immunity Seminar Series Individual talk microRNAs and Immune Regulation 30.03.2015 Montreal, Canada Jeker Lukas;
Mini Symposium on the Frontier of T and B Lymphocyte Biology and Clinical Application, Institut Pasteur of Shanghai, Chinese Academy of Science Talk given at a conference The microRNA cluster miR-17-92 is a critical regulator of Treg and TFH biology 05.11.2014 Shanghai, China Jeker Lukas;


Self-organised

Title Date Place
DBM Genome Editing Club (monatliches Seminar) 01.10.2014 Departement Biomedizin, Basel, Switzerland

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Tag der Biomedizin Poster 09.04.2016 Basel, Switzerland Gorka Oliver; Jeker Lukas;
Tag der Biomedizin Talk 09.04.2016 Basel, Switzerland Jeker Lukas;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Transplantationsimmunologie - von Zellen, Drohnen und Genen (öffentliche Antrittsvorlesung) German-speaking Switzerland 2018
Talks/events/exhibitions Klein - aber bedeutend (Habilitationsvorlesung) German-speaking Switzerland 2017
Talks/events/exhibitions Tag der Biomedizin German-speaking Switzerland 2016

Associated projects

Number Title Start Funding scheme
176986 The Role of microRNAs in Immune Regulation 01.03.2018 SNSF Professorships

Abstract

Regulatory T cells (Treg) are essential for the establishment and maintenance of immune homeostasis. Due to their proven ability to prevent and even cure autoimmune diseases and their important role in preventing rejection of transplanted organs in preclinical animal models, Treg have entered clinical trials. In contrast, T follicular helper (Tfh) cells provide classic "help" to B cells and promote autoimmunity. microRNAs are posttranscriptional regulators of gene expression. Using in vivo gene ablation we have demonstrated that Treg and Tfh depend on miRNA function in vivo. Specifically, we showed the importance of the miRNA cluster miR-17-92 for Treg and Tfh function. It is intriguing that miR-17-92 regulates both, promoters and inhibitors of immune responses, respectively. We propose to investigate cellular contexts in which miR-17-92 is important and to define molecular mechanisms by which miR-17-92 regulates T cell function. I expect that by studying miRNAs and their target genes we will significantly advance our understanding of immune regulation.
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