euroinflammation and pain in a mouse model for Fabry disease

Project Title: Neuroinflammation and pain in a mouse model for Fabry disease


Early Stage Researcher 6 – Jeiny Choconta

Individual Research Project 6
Project Title: Neuroinflammation and pain in a mouse model for Fabry disease
Supervisor: Prof. M. Kress (MUI)
Co-supervisor(s): Dr. M. Langeslag (MUI) and Prof. R. Chaudhuri (KCL, clinical)

Project Manager Tobeatpain

Prof. M. Kress (MUI)

Project Manager Tobeatpain

Dr. M. Langeslag (MUI)

Project Manager Tobeatpain

Prof. R. Chaudhuri (KCL, Clinical)

Objectives


Fabry disease (FD) is an X-linked lysosomal storage disorder due to deficiency of the enzyme α-galactosidase A (αGal), which leads to accumulation of neutral glycosphingolipids, mainly globotriaosylceramide (Gb3). Peripheral blood monocytes from FD patients present with high cytokine expression and production, and Gb3 and toll like receptor 4 (TLR4) are involved in this phenotype. To generate new hypotheses on the pathogenesis of FD pain, this project will evaluate innate immune system-mediated regulation of cytokine expression in the peripheral nerve, spinal cord and brain.

ESR 6 will:

  1. Assess macrophage infiltration and microglia activity in dorsal root ganglia (DRG), spinal cord and brain (IHC) in a mouse model of FD;
  2. Explore cytokine mRNA and microRNA expression profiles and perform associated target gene analysis (qPCR) in DRG, peripheral nerve, spinal cord and brain;
  3. Identify mechanistic pathways through a bioinformatics approach;
  4. Validate specific FD related new targets as well as cytokines and microRNAs in vivo (behaviour using pharmacological blockers/activators followed by expression analysis).

Expected results


Definition of the role of microRNAs and cytokines in macrophages/microglia-mediated mechanisms and identification of novel targets that underlie pain symptoms in FD.

Secondment(s): Eli Lilly (6 months). Bioinformatics tools to identify significant mechanistic pathways, and training on product development strategy, product launch & management, public relations.

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This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Grant Agreement No 764860.