Pharmacological targeting of sphingosine 1-phosphate receptors to promote remyelination in Alzheimer’s disease and multiple sclerosis

Summary

In this project you will investigate a new molecular pathway that is required for normal myelin formation, and the therapeutic potential of targeting this pathway to promote remyelination in Alzheimer's disease and multiple sclerosis. We have recently discovered this new molecular pathway centered on sphingosine 1-phosphate (S1P).

Supervisor(s)

Associate Professor Anthony Don

Research Location

Camperdown - Charles Perkins Centre

Program Type

Masters/PHD

Synopsis

Demyelination is one of the two defining pathological features of multiple sclerosis (along with inflammation), leading to loss of neurological functions. Existing therapeutics for multiple sclerosis suppress the neuroinflammation that characterises the disease, but do not promote restoration of function through re-myelination. Current research is starting to explore re-myelinating therapies.My research group research is beginning to uncover the tremendous significance of age-related demyelination in Alzheimer's disease, with the suggestion that re-myelinating therapies could form an important therapeutic tool for this disease as well (there are currently no good therapeutic treatments for Alzheimer's disease).

Sphingosine 1-phosphate (S1P) receptor agonists, specifically the drug Fingolimod, are used clinically in the treatment of multiple sclerosis. The primary mode of action of this class of drugs is immunosuppression, whereby they trap lymphocytes in the lymph nodes and prevent them from reaching sites of inflammation. S1P is a small lipid signalling molecule that is essential for life and an important physiological regulator of immune responses, vascular biology, and neurological functions. Recent research indicates that S1P receptor agonists such as Fingolimod may also directly stimulate re-myelination, possibly mediated through activation of the S1P5 receptor on oligodendrocytes and Schwann cells, which are the myelinating cells.

In this research project, you will investigate a new molecular pathway that my research group has uncovered, involving the S1P5 receptor. The aims are to determine if endogenous S1P is required for normal myelin maintenance and function, and if re-myelination can be promoted using specific pharmacological agonists of the S1P5 receptor. Needless to say, there is tremendous potential for this research to be applied clinically in the future.

The research will employ sophisticated genetic mouse models, in which we will delete specific genes in specific brain cell types, cutting edge mass spectrometry, immunohistochemistry, and electron microscopy. As such, you will gain experience with a broad array of modern biochemical and molecular techniques.

Additional Information

I run a focused and supportive research team including students, postdocs, and a research assistant. You will have plenty of support for your PhD studies, and access to the most sophisticated equipment and resources.A top-up payment of $6000 will be made for any candidates who have their own scholarship. For those candidates with a good first class or high scoring second class honours who have not received a competitive government scholarship, please see me and I will discuss the possibility of funding a scholarship.

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Keywords

Alzheimer’s disease, multiple sclerosis, Pharmacology, Lipid, myelin, brain, myelination, therapy

Opportunity ID

The opportunity ID for this research opportunity is: 2368

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