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Mechanisms to improve glucocorticosteroid efficacy in neuroimmunological disease

English title Mechanisms to improve glucocorticosteroid efficacy in neuroimmunological disease
Applicant Chan Andrew
Number 172952
Funding scheme Project funding (Div. I-III)
Research institution Universitätsklinik für Neurologie Inselspital Universität Bern
Institution of higher education University of Berne - BE
Main discipline Immunology, Immunopathology
Start/End 01.12.2017 - 30.11.2021
Approved amount 429'000.00
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Keywords (7)

JNK; Experimental autoimmune Encephalomyelitis; Glucocorticoid receptor; Vitamin D; mTOR; Glucocorticoid resistance; Multiple Sclerosis

Lay Summary (German)

Lead
Die Kortison Pulstherapie stellt die Therapie akuter entzündlicher Schübe bei neuroimmunologischen Erkrankungen wie der Multiplen Sklerose (MS) dar. Dieses Forschungsvorhaben untersucht Mechanismen, die die Effektivität der Kortison Pulstherapie verbessern.
Lay summary

Projekttitel

Multiple Sklerose: Strategien zur Verbesserung der Wirksamkeit des Kortisons

 

Hauptgesuchsteller

Prof. Dr. med. Andrew Chan

Universitätsklinik für Neurologie, Inselspital, Universität Bern

Hintergrund

Trotz der Kortison Pulstherapie heilen bei einem großen Teil der Patienten Symptome akuter MS-Schübe nur unzureichend aus, welches zu einer Zunahme der Behinderung führt. Wir haben bereits gezeigt, dass Vitamin D biologische Effekte des Kortisons verstärkt. Diese Effekte werden durch einen Vitamin D bedingten Anstieg des zellulären Kortisonrezeptors vermittelt. Die Untersuchung zugrunde liegender molekularer Signalwege ist die Grundvoraussetzung dafür, diesen Mechanismus therapeutisch nutzbar zu machen.

 

Das Ziel

Ziel dieses Projektes ist es, Signalwege zu charakterisieren, die dem funktionellen Synergismus zwischen Vitamin D und Glukokortikosteroiden zugrunde liegen. Dabei stehen aufgrund unserer Vorarbeiten insbesondere der mTOR- als auch der JNK-Signalweg im Zentrum. Hierbei werden entsprechende molekulare Mechanismen im Zellkultur- und im Tiermodell untersucht.

 

Bedeutung

Die Ergebnisse sollen dazu beitragen Biomarker für ein unzureichendes Ansprechen/Resistenz auf eine Kortisontherapie zu charakterisieren und gleichzeitig potentielle therapeutische Ziele zur Steigerung der Wirksamkeit des Kortisons zu identifizieren.

 


Direct link to Lay Summary Last update: 22.04.2017

Responsible applicant and co-applicants

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Abstract

Background: Glucocorticosteroids (GCs) are widely used for the treatment of autoimmune disorders. In multiple sclerosis (MS), high dose intravenous GC-“pulse” therapy serves as the mainstay in the treatment of acute relapses. Still, a considerable proportion of patients does not improve sufficiently even to repeated, dose-escalated GC-pulse therapy. Incomplete remission from relapse is a major reason for disability in more than 40% of the patients. In previous work we have demonstrated that vitamin D (VD) increases cellular GC effects in vitro and augments GC-efficacy in experimental autoimmune encephalomyelitis (EAE), an animal model reflecting aspects of MS. These synergistic effects were mediated by VD-dependent upregulation of the glucocorticosteroid receptor (GR) in T cells. On a molecular level, VD inhibited mTORc1 (mammalian target of rapamycin) signal transduction, VD levels were inversely associated with mTORc1 signalling in T cells from MS patients, and mTORc1-inhibitor everolimus demonstrated therapeutic synergism with GC in EAE. However, definite proof of mTORc1-inhibition as a mechanism to increase GC-efficacy and potentially more potent and specific pharmacological targeting of mTORc1 are lacking. Hypothesis: We hypothesize that a) specific inhibition of mTORc1 synergistically increases GC-efficacy in vitro and in vivo; b) this effect is mediated via the GR-complex; c) more potent and specific mTORc1-inhibition using agents clinically in use in other indications exhibits higher therapeutic efficacy than VD in combination with GC; and d) JNK (c-Jun N-terminal kinase)-inhibition may exhibit additional synergistic effects with GC. Methods: We propose a translational approach from in vitro studies to application in EAE and validation of key findings using biomaterial from selected MS patients. We will address specific members of the GR-complex altered during GC-resistant MS relapse, dynamic changes during neuroinflammation and regulation of GR-complex by mTOR-, JNK-inhibitors and VD (work package WP 1). These substances will then be investigated for synergistic effects with GC using functional readouts associated with GC-efficacy in cells from MS patients with differential relapse response to GCs. Therapeutic synergistic efficacy will be addressed in EAE, with VD as control. Proof of central GR-involvement will be obtained in animals with T cell specific GR-deletion. Selective involvement of proposed pathways will be investigated in animals with T cell specific mTORc1 deletion and animals with JNK2 deficiency (WP 2). Finally, data will be corroborated by a target gene expression approach covering GR-, mTOR- and JNK-pathways in patients with differential MS relapse response to GCs (GC-resistant, GC-responsive), stable MS and controls. This data will also be used for a multivariate analysis to identify markers that predict GC-resistance during MS relapse (WP 3). Perspectives: We expect the data to provide new insights into the pathomechanisms of GC-resistance leading to the identification of new biomarkers and therapeutic targets alike. Specific mechanistic pathways will be corroborated by genetic approaches as well as stepwise selection of pharmacological inhibitors using cells from selected MS patient groups and the animal model. Given that inhibitors of mTOR-pathways investigated here are already in clinical use, our data carries the potential of rapid translation to improve MS relapse therapy. Addressing mechanisms to overcome GC-resistance may also have implications for other diseases.
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