Antibody-mediated activation of microglia and astrocytes: a strategy to enhance remyelination in progressive multiple sclerosis

Stimulating remyelination by endogenous oligodendrocyte progenitor cells (OPC) is an attractive strategy to restore axonal function and halt accumulation of disability in progressive multiple sclerosis (PMS). Exciting new data indicate this goal may be achieved using components of the natural antibody repertoire. This concept derives from experiments demonstrating lipid-reactive components of natural (germ line) immunoglobulin repertoire can induce interferon-beta and genes encoding pro-myelinating factors (IL-11, LIF, CNTF) in myelinating cultures. Preliminary data indicate this non-lytic, complement independent-effect is initiated by antibody-mediated induction of Ifnb in microglia which then triggers type 1 interferon receptor-dependent induction of “pro-myelinating” genes in astrocytes.
This project will exploit the joint expertise of our laboratories to define the mechanistic basis of this response and assess its therapeutic potential for remyelination by:
1) Quantifying antibody-mediated remyelination: (i) in vitro using organotypic brain explants, and (ii) focal toxin-induced demyelination in vivo.
2) Assessing associated changes in gene expression in microglia and astrocytes isolated by flow cytometry from remyelinating lesions in the presence or absence of specific antibody.
3) Correlating expression of candidates identified as being regulated in microglia/astrocytes with remyelination efficiency in MS post-mortem tissue lesions by immunohistochemistry and/or in situ hybridization.
4) Defining the biological relevance of this effect by inhibition of pathways identified in (2) e.g. using pharmaceutical inhibitors.

Prerequisites
First or Upper second class degree with specialization in Immunology and/or Neuroscience
Basic knowledge of Microsoft Office (Word, Excel, Powerpoint)
Minimum 3 month work experience in neuroscience or immunology-related research.
Please contact your intended supervisor to discuss the project and your suitability for it before submitting your application.

The project is a part of SPRINT-MND/MS, a new Scotland-wide PhD scheme for research into motor neurone disease and multiple sclerosis. Projects, encompassing a wide range of topics including laboratory, clinical, and social sciences, are available at Aberdeen, Dundee, Edinburgh, Glasgow and St Andrews Universities. This exciting initiative provides a great opportunity for budding researchers in any field related to MND or MS to join Scotland’s network of world-leading scientists and health professionals. Find more information here: http://www.edneurophd.ed.ac.uk/sprint-mndms-phd-programme

Project start date September 2017