Project No. 2301
Dr Melissa Andrews – University of Southampton
Prof Arthur Butt – University of Portsmouth
Damage to the central nervous system (CNS, brain and spinal cord), results in irreversible neurodegeneration and irrevocable loss of function.
This can occur following an accident, vascular event, sports injuries and is a major factor in natural aging. Axon regeneration in the CNS does not occur because glial cells form a scar tissue that is inhibitory for axon growth. To achieve targetted axon regeneration, it will require combinatorial approaches involving cell transplantation to replace damaged cells and promote repair, using various cell types, such as stem cells and glial cells. In this context, olfactory ensheathing cells (OECs) have many advantages, because they are specialised glial cells that provide trophic factors and cellular bridges that promote and target growth of olfactory axons into the brain throughout life. Equally as promising in terms of regenerative growth is the re-expression of integrin receptors which have been shown to be essential for neuronal outgrowth and axonal pathfinding during development but are downregulated with maturation. Re-expression of integrin receptors in vivo using viral vectors has demonstrated promising results in dorsal column axon regeneration, however data also indicates that these integrins do not transport effectively from cell body to axon/growth cone within the main motor pathway, the corticospinal tract, thereby minimising their growth-promoting ability. Recently we have generated integrin-expressing exosomes from HEK293 cells and demonstrated that these exosomes induce significant outgrowth in cultured dorsal root ganglia neurons (DRGs) on inhibitory substrates. Therefore, this studentship project aims to develop exosomes from a more physiological source, namely OECs, which can be modified to express growth-promoting receptors including integrins.
Specifically, this PhD project will provide training in cellular assays to test the hypothesis that integrin-expressing exosomes derived from neural sources will induce a significant growth response in cultured primary neurons grown on or in the presence of inhibitory extracellular matrix and ex vivo in brain slice and spinal cord slice models.
Candidates with a strong interest in neuronal cell biology, microscopic imaging, and regenerative medicine are encouraged to apply