Project

Back to overview

Immune regulation by microRNAs in Multiple Sclerosis-Added value in characterization of disease course and response to treatment

English title Immune regulation by microRNAs in Multiple Sclerosis-Added value in characterization of disease course and response to treatment
Applicant Lindberg-Gasser Raija Liisa Päivikki
Number 160168
Funding scheme Project funding (Div. I-III)
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Clinical Immunology and Immunopathology
Start/End 01.01.2016 - 31.12.2019
Approved amount 378'929.00
Show all

All Disciplines (2)

Discipline
Clinical Immunology and Immunopathology
Immunology, Immunopathology

Keywords (5)

prognosis; multiple sclerosis; treatment response; microRNA; Immune regulation

Lay Summary (German)

Lead
MikroRNAs sind kurze, einzelsträngige RNA-Moleküle. Diese Moleküle regulieren mehr als 50% aller protein-kodierenden Gene und fungieren somit als Schlüsselregulatoren bei einer Vielzahl biologischer Prozesse. In der Pathogenese von Multipler Sklerose (MS) spielen microRNAs eine wichtige Rolle. So konnten wir und auch andere zeigen, dass verschiedene microRNAs in bestimmten Immunezellen von MS Patienten vermehrt bzw. vermindert exprimiert werden. Interessanterweise kommen miRNAs nicht nur innerhalb der Zelle vor, sondern auch extrazellulär in Körperflüssigkeiten wie Serum, Plasma, Liquor (CSF), Tränen und Urin.
Lay summary

In diesem Projekt befassen wir uns mit zwei wesentlichen Fragen:

 

1. Können extrazelluläre, zirkulierende microRNAs als nützliche Marker hinsichtlich einer eindeutigen Krankheitsdiagnose, insbesondere im Hinblick auf die verschiedenen Subtypen der MS dienen? Kann zudem die Bestimmung der microRNA-Expessionsmuster bei der Prognose des Krankheitsverlaufes und der Effektivität der gewählten Behandlung helfen?

 

2. Welche Rolle spielen extrazelluläre microRNAs bei der Immunpathogenese von MS?

            Hier fokusieren wir uns auf extrazelluläre Vesikel (EV) in Serum und CSF. Diese Vesikel transportieren Moleküle wie microRNAs und mRNAs und können somit bei der Interaktion verschiedener Zelltypen eine Rolle spielen. Durch Zellkultur-Experimente mit primären Lymphozyten soll dann die Funktionalität der aus MS-Patienten und gesunden Kontrollpersonen isolierten EVs analysiert werden.

 

Klinische Relevanz und wissenschaftliche Bedeutung:

Bis heute gibt es keine zuverlässigen Biomarker, die eine eindeutige Vorhersage des Krankheitsverlaufes bei MS zulassen. Das Ziel dieses Projektes ist daher, neue Prognose-Möglichkeiten aufzuzeigen, die eine solche Vorhersage ermöglichen können.

Direct link to Lay Summary Last update: 16.12.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
PARP-1 deregulation in multiple sclerosis.
MeiraMaria, SieversClaudia, HoffmannFrancine, BodmerHeidi, DerfussTobias, KuhleJens, HaghikiaAiden, KapposLudwig, LindbergRaija LP (2019), PARP-1 deregulation in multiple sclerosis., in Mult Scler J Exp Transl Clin, 5(4), 1-8.
Natalizumab-induced POU2AF1/Spi-B upregulationA possible route for PML development
Meira Maria, Sievers Claudia, Hoffmann Francine, Haghikia Aiden, Rasenack Maria, Décard Bernhard F., Kuhle Jens, Derfuss Tobias, Kappos Ludwig, Lindberg Raija L.P. (2016), Natalizumab-induced POU2AF1/Spi-B upregulationA possible route for PML development, in Neurology - Neuroimmunology Neuroinflammation, 3(3), e223-e223.

Collaboration

Group / person Country
Types of collaboration
Prof Matthias Wymann/Biochemistry/DBM Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof Lukas Jeker, Immunoregulation/DBM 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
Weekly MS-Sitzung Individual talk Exosomes in MS - What we know and what we still want to know 03.12.2019 Basel, Switzerland Lindberg-Gasser Raija Liisa Päivikki; Meira Maria;
The 34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Poster Defining extracellular RNA (exRNA) expression as an indicator for natalizumab treatment response and PML risk assessment in multiple sclerosis 10.10.2018 Berlin, Germany Meira Maria; Lindberg-Gasser Raija Liisa Päivikki;
ISEV 2018, International Society of Extracellular Vesicles Annual Meeting Poster Exploring the role of Extracellular Vesicles (EVs) in immune response 02.05.2018 Barcelona, Spain Breitling Ritz Simone; Lindberg-Gasser Raija Liisa Päivikki;
Immunomeeting Individual talk MiRNA/mRNAs: indicators of immune regulation and treatment response in Multiple Sclerosis 12.02.2018 Basel, Switzerland Lindberg-Gasser Raija Liisa Päivikki; Meira Maria;
Multiple Sclerosis Researcher Meeting (SMSG) Individual talk Extracellular RNA (exRNA) signature as an indicator for natalizumab treatment response and PML risk assessment 26.01.2018 Luzern, Switzerland Lindberg-Gasser Raija Liisa Päivikki; Meira Maria;
Scientific advisory meeting Individual talk Extracellular RNA (exRNA) - The role in Multiple Sclerosis 18.01.2018 Basel, Switzerland Meira Maria; Kappos Ludwig; Lindberg-Gasser Raija Liisa Päivikki; Breitling Ritz Simone;
Neurology Research Retreat Individual talk Extracellular vesicles (EVs) – Do they have an importance in Multiple Sclerosis? 14.12.2017 Basel, Switzerland Meira Maria; Lindberg-Gasser Raija Liisa Päivikki; Breitling Ritz Simone;
University Basel Immunology Community (UbiCo) Retreat Poster Exploring the role of Extracellular Vesicles (EVs) in immune response 01.11.2017 Engelberg, Switzerland Breitling Ritz Simone; Lindberg-Gasser Raija Liisa Päivikki;
The 7th Joint Congress of the European and Americas Committees on Treatment and Research in Multiple Sclerosis (ECTRIMS and ACTRIMS) Poster PARP-1 deregulation in Multiple Sclerosis 25.10.2017 Paris, France Meira Maria; Lindberg-Gasser Raija Liisa Päivikki;
Swiss-French MS Meeting Poster Functional importance of extracellular vesicles (EVs) in immune regulation of Multiple Sclerosis (MS) 09.06.2017 Paris, France Meira Maria; Lindberg-Gasser Raija Liisa Päivikki; Breitling Ritz Simone;
Neurology Research Retreat Individual talk PML under Natalizumab therapy; searching for immunological markers 01.12.2016 Basel, Switzerland Lindberg-Gasser Raija Liisa Päivikki; Meira Maria;
University Basel Immunology Community (UbiCo) Retreat Poster Exploring the role of extracellular vesicle-derived microRNAs/mRNAs in immune response of Multiple Sclerosis - Work in progress 01.11.2016 Engelberg, Switzerland Lindberg-Gasser Raija Liisa Päivikki; Breitling Ritz Simone;
University Basel Immunology Community (UbiCo) Retreat Individual talk Extracellular transcriptomics - Importance in immune regulation of Multiple Sclerosis? 01.11.2016 Engelberg, Switzerland Lindberg-Gasser Raija Liisa Päivikki;
The 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Poster Emerging role of extracellular vesicle-derived microRNAs/mRNAs in immune response of Multiple Sclerosis-work in progress 14.09.2016 London, Great Britain and Northern Ireland Meira Maria; Lindberg-Gasser Raija Liisa Päivikki; Breitling Ritz Simone;
Neuroimmunology seminars Individual talk (Extra)cellular ncRNAs - Importance in immune pathogenesis of Multiple Sclerosis 08.06.2016 University hospital Zürich, Switzerland Lindberg-Gasser Raija Liisa Päivikki;


Associated projects

Number Title Start Funding scheme
132644 Immune regulation by microRNAs in Multiple Sclerosis - Added value in characterization of disease course and response to treatment 01.01.2011 Project funding (Div. I-III)

Abstract

1SummaryBackground: MicroRNAs (miRNAs) are short single-stranded RNA molecules, which modulate gene-expression of >30% of all protein-encoding genes and are key regulators of a wide variety of biological processes. They are highly expressed both in cells of the immune and the central nervous system (CNS). Deregulation of miRNAs has been associated with cancer, neurodegeneration and autoimmunity. Indeed, emerging evidence underlines an involvement of miRNAs in the pathogenesis of Multiple Sclerosis (MS). We and others have shown deregulation of miRNAs in various subpopulations of immune cells in MS. MiRNAs are not only intracellular molecules, but they are also found in various body fluids, like serum, plasma, cerebrospinal fluid (CSF), urine and tears. Because miRNAs are present in circulation in a stable form that is protected from endogenous RNAse activity they have great potential as biomarkers in various disorders.Aims: In this proposal we address two questions:1)Are extracellular circulating miRNA expression patterns valuable indicators in MS, in terms of disease diagnosis, sub-classification according to disease courses, stage and progression rate, and/or treatment response?We will compare miRNA signatures in serum in matched healthy volunteers (HV) with well characterized groups of RR, SP and PP MS. An important goal is to identify early marker(s) of the conversion from relapsing-remitting to the progressive phase of the disease. Furthermore, we’ll study the impact of treatment with natalizumab, BG12 (dimethylfumarate), teriflunomide and fingolimod on miRNA expression patterns in MS patients and their relation to treatment response.2)What is the role of extracellular miRNAs in the immune pathogenesis of MS?In this part of the project, we’ll focus on the characterization of the extracellular vesicles (EV), carrying e.g. miRNAs, and mRNAs, in serum and CSF from MS patients and healthy subjects. First we’ll investigate, if the quantity and miRNA load of EVs is different in MS compared to HV. By cell surface marker staining for various immune cells, but also neuronal cells, we aim to characterize the origin of the MPs in serum and CSF to get more insights into the path between periphery and CNS. Cellular experiments by delivery of EVs, isolated from MS patients and HVs, into primary lymphocyte cultures, will be performed to assess the functionality of EVs, aiming at getting more insights into the importance of EVs in the immune pathogenesis in MS. Methods: Low-density fluidic cards and next generation sequencing technologies will be used to analyze the expression patterns of small ncRNAs and mRNAs in serum and CSF. The other technologies include real time (RT-PCR) assays, peripheral blood mononuclear cell (PBMC), T- and B cell cultures, NTA-(nanoparticle tracking analysis), transfection assays, flow-cytometer, enzyme linked immunoassays, ELISA, multiplex RNA/protein analysis, Western blot, confocal microscopy.Clinical relevance and scientific significance:There is an unmet need for reliable prognostic biomarkers for management of MS. This project aims at providing new innovative tools for predictive monitoring of various attributes of MS. This project will also yield novel insights in gene regulation, the molecular mechanisms of MS activity and progression and better understanding of immune regulation in MS. A better characterisation of different disease courses, disease activity states and progression as well as treatment related changes in miRNA expression profiles may provide a better basis for phase adapted and better targeted therapies. Furthermore, this approach can serve as a basis for the identification of biomarkers in other diseases, particularly ones in which there is interplay between the immune and nervous system.
-