Identification of PSA-NCAM Modulators

Funding – self-funded/externally sponsored applicants  (PhD Fees can be found here)

• Applications are accepted year round
• Standard Entry dates – January and September
• Applicants are expected to have a degree (equivalent of Honours or Masters) in a relevant discipline.

Neural cell adhesion molecule (NCAM) belongs to the immunoglobulin superfamily of cell adhesion molecules. They are expressed in the brain and associated with adhesions between neurons and glial cells. NCAM carries a specific post-translational modification that adds polysialic acid (PSA) to the extracellular compartment of the NCAM molecule. PSA is a long, linear alpha2,8-linked carbohydrate molecule. The amount of PSA-NCAM on the cell surface is regulated by both the addition of PSA onto NCAM, and through an endocytosis-driven internalisation and rapid degradation of the polysialic acid. The addition is conducted by enzymes ST8SiaII (STX) and ST8SiaIV (PST), two Ca2+-dependent Golgi-complex-associated polysialyltransferases. This results in the presence of large negatively charged hydrophilic molecules on the cell surface, which causes steric impediments with receptors and the extracellular matrix (ECM) molecules, diminishing cell-adhesion and ECM interactions.

PSA-NCAM is most prominently expressed in the developing nervous system where it promotes the migration of neural and non-neural precursors, as well as facilitating axonal pathfinding and synaptogenesis. With regards to adult brain function, PSA-NCAM is involved in brain tumour invasion and migration and also in Alzheimer's disease there are deficiencies in PSA-NCAM in areas of high plasticity and early affected brain regions.

The proposed study will look for PSA-NCAM modulators by testing PSA-NCAM levels by phenotypically screening the impact of a wide range of compounds in the search for modulators. Our hypothesis is that modulation of PSA-NCAM may hold therapeutic value either for brain tumours or neurodegenerative diseases.

Specific questions:

What classes of compounds up or down regulate PSA-NCAM levels?

What is the activity of these compounds - do they change the polysialylation rate, or do they alter the desialylation rate?

What are the targets of PSA-NCAM-modulating compounds?

How can in silicon modelling be used to create analogues of PSA-NCAM modifiers

The skills a student would develop are:

Cell culture, high throughput drug screening, cytology, high throughput imaging, in silico modelling, synthetic/medicinal chemistry.