Defining the role of the talin-kindlin-integrin axis in the regulation of neurite outgrowth.

Spinal cord injury (SCI), either from physical trauma or disease/degeneration, disrupts the communication between the brain and the rest of the body which can result in life-changing disability. Currently there are no clinical treatments to regenerate axons after SCI. Integrin receptors are a core component of the cell migration machinery that is essential to drive neuronal outgrowth and axonal pathfinding during development to "wire up" the neurons correctly. Regeneration fails in part due to alpha9 integrin receptor expression being switched off in the adult nervous system. Damaged neurons are thus unable to mount a regenerative response against lesion-induced upregulation of extracellular matrix molecules, such as tenascin-C, the ligand for alpha9 integrin (alpha9). This deficit can be partially rescued upon re-expression of alpha9 which we have shown to significantly enhance axonal regeneration of dorsal root and dorsal column axons. However, although re-expression of these vital receptors results in a positive growth response, alpha9-induced regrowth was limited to the site of injury. The activation state of integrin receptors is also critical as inactive integrins do not induce growth. Spinal cord lesion sites have increased levels of myelin debris and chondroitin sulfate proteoglycans, and both have been shown to inactivate integrins, further impeding repair. This effect can be rescued with the use of an intracellular integrin activator known as kindlin-1. Likewise, another integrin activator, talin, has been shown to have a positive growth response on neurons, however further investigation into this interaction is needed to optimise and maximise the growth response to induce significant regeneration.
This PhD project will provide cutting-edge multidisciplinary training in cellular assays and neuroscience (Andrews) with biophysics and biochemistry (Goult) to test the hypothesis that the talin-kindlin-integrin axis regulates neurite outgrowth in a regulatable way, and activation of this pathway might enable novel approaches to treat spinal injury.