Early Stage Researcher 6 – Jeiny Luna-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)

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).

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.