Multiple Sclerosis Laboratory

L to R: Dr Helmut Butzkueven and Professor Trevor Kilpatrick
L to R: Dr Helmut Butzkueven and Prof Trevor Kilpatrick

Group Leader

Professor Trevor J. Kilpatrick MB BS (Melb) PhD (Melb) FRACP

Contact Details

Email:

trevor.kilpatrick@florey.edu.au

Phone:

+61 (0)3 8344 1804

Fax:

+61 (0)3 9349 5917

Number of

Staff:        16
Students:  8

Research Interests

The Multiple Sclerosis Group is focused on developing strategies to limit the severity of demyelinating diseases of the central nervous system, of which multiple sclerosis (MS) is the most common cause. Multiple sclerosis is thought to result from an autoimmune attack against myelin, which is produced by specialised glial cells known as oligodendrocytes that ensheath neurons. While currently available therapies have some capacity to reduce disease activity via immunomodulatory mechanisms there are, as yet, no established treatments that either reduce oligodendrocytic damage or enhance nervous system repair, strategies that our laboratory is focusing upon. Such strategies include attempts to promote oligodendrocyte survival and/or to promote neural precursor cell recruitment to the oligodendrocyte lineage. Our work focuses on both of these areas.

In particular, our aims are:

Major Research Projects

Identifying growth factors that potentiate oligodendrocyte survival in demyelinating disease

Using the animal model experimental autoimmune encephalomyelitis (EAE), which produces an inflammatory attack targeting oligodendrocytes and myelin similar to a relapse of MS, we have previously demonstrated that the cytokine Leukemia Inhibitory Factor (LIF) is an integral part of the central nervous system’s injury response. Specifically, the brain produces LIF during auto-immune attacks and this promotes survival of oligodendrocytes and myelin integrity. Interfering with this endogenous response leads to more severe demyelination and increased oligodendrocyte loss, and treatment with additional, therapeutic LIF reduces oligodendrocyte death and EAE disease severity.

Building on this knowledge, Dr Helmut Butzkueven within the group has been investigating the molecular mechanism of action of LIF. Surprisingly, we have discovered that treatment of mature oligodendrocytes with LIF results in increased expression of genes involved in cytokine secretion and in the expression of the neuro-peptide galanin. We are currently investigating whether this LIF-induced galanin production is directly responsible for promoting oligodendrocyte survival and for limiting myelin damage in animal models of MS.

Michele Binder has shown that genes encoding three members of a receptor protein tyrosine kinase family (Axl, Mer and Tyro3), and their common ligand Gas6, are regulated in an animal models of demyelination and that Gas6 promotes the viability of oligodendrocytes in vitro. We are currently exploring the relationship between Gas6 signalling, microglial activity and oligodendrocyte survival during demyelination utilising Gas6 knockout mice.

Investigating the molecular regulation of neural precursors in demyelinating disease

We recognise that neural precursor cells, recently identified to be present within the subventricular zone of the adult mammalian brain, are a potential source to replenish oligodendrocytes that are lost in the context of demyelinating disease. Dr Holly Cate has used laser capture microdissection and microarray analysis to interrogate the genes that are regulated by cells within the SVZ after delivery of a demyelinative insult. We have found that many of the significantly regulated genes formed an interconnected network directly linked to the transforming growth factor beta (TGFß) pathway. In vitro assays are currently being used to assess the effects of TGFß family members (TGFßs, BMPs, and Activins) on proliferation, differentiation, and survival of oligodendroglia and SVZ-derived neural precursors.

Our group has also established that cytokines such as LIF and ciliary neurotrophic factor that signal through the LIFRb/gp130 receptor complex, promote the self-renewal of embryonic and adult neural precursor cells (NPCs). We have also identified that the Suppressor of Cytokine Signalling-3 (SOCS3) protein negatively regulates LIF signalling signalling in these cells. Dr Tobias Merson in the group is currently investigating whether these signalling pathways are important in influencing the capacity of NPC to repair the demyelinated brain.

Analysis of the regenerative response to demyelination

We are also developing transgenic approaches to definitively label both mature oligodendrocytes and precursor cells in the adult animal, prior to exposure to a demyelinative insult. In this way, we will be able to assess the relative contribution of each cell type to the remyelinative process.

Magnetic Resonance Imaging (MRI) Analysis of Pathology in Mouse Models of Central Demeylination

There is a need to develop reliable and valid surrogate markers of key elements of the neuropathology of animal models of MS in order to efficiently assess the efficacy of putative neuroprotective or regenerative agents. The most obvious technology to develop for this purpose is magnetic resonance imaging (MRI), concentrating on its capacity to identify the extent of demyelination and the degree of axonal degeneration. The development of such technologies will enable not only high throughput screening but should also facilitate translational research via application of the same technology in humans to assess the efficacy of agents shown to be of therapeutic benefit in the mouse. We are undertaking this work in collaboration with A/Prof Gary Egan and to do so are assessing two animal models; firstly, cuprizone-challenge in which robust demyelination occurs within the corpus callosum and secondly, optic neuritis in animals with experimental autoimmune encephalomyelitis.

Laboratory Techniques

Funding

Research