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

脊髓损伤(SCI)，无论是由身体创伤或疾病/退化引起的，扰乱了大脑和身体其他部分之间的沟通，可能导致改变生活的残疾。目前还没有临床上治疗脊髓损伤后再生轴突的方法。整合素受体是细胞迁移机制的核心组成部分，在发育过程中驱动神经元生长和轴突寻路，以正确地连接神经元。再生失败的部分原因是成人神经系统中整合素α9受体的表达被关闭。因此，受损的神经元无法对损伤诱导的细胞外基质分子的上调产生再生反应，例如alpha9整合素(Alpha9)的配体tenascin-C。这种缺陷可以在重新表达Alpha9后部分修复，我们已经证明，Alpha9可以显着增强背根和背柱轴突的轴突再生。然而，虽然这些重要受体的重新表达导致了积极的生长反应，但α9诱导的再生仅限于损伤部位。整合素受体的激活状态也是至关重要的，因为不活跃的整合素不会诱导生长。脊髓损伤部位髓鞘碎片和硫酸软骨素蛋白多糖水平增加，两者都被证明使整合素失活，进一步阻碍修复。这种效应可以通过使用一种称为kindlin-1的细胞内整合素激活剂来挽救。同样，另一种整合素激活剂talin已被证明对神经元具有积极的生长反应，但这种相互作用需要进一步研究，以优化和最大化生长反应，以诱导显著的再生。这个博士项目将提供细胞分析和神经科学(Andrews)与生物物理和生物化学(Goult)的尖端多学科培训，以检验talin-kindlin-Integrin轴以可调节的方式调节轴突生长的假设，这一途径的激活可能使治疗脊髓损伤的新方法成为可能。

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.