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

定义talin-kindlin-整合素轴在神经突生长调节中的作用。

• 批准号: 2596704
• 金额: --
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2596704
• 关键词: Defining; role; talin; kindlin; integrin

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.

脊髓损伤（SCI），无论是身体创伤还是疾病/变性，都会破坏大脑与身体其他部分之间的沟通，从而导致改变生活的残疾。目前还没有临床治疗方法来再生SCI后的轴突。整合素受体是细胞迁移机制的核心组成部分，其对于在发育期间驱动神经元生长和轴突寻路以正确地“连接”神经元是必不可少的。再生失败的部分原因是α 9整合素受体表达在成人神经系统中被关闭。因此，受损的神经元不能对损伤诱导的细胞外基质分子（例如，生腱蛋白-C，α 9整联蛋白（α 9）的配体）的上调产生再生反应。这种缺陷可以在α 9的重新表达后部分挽救，我们已经证明α 9显著增强背根和背柱轴突的轴突再生。然而，尽管这些重要受体的重新表达导致了积极的生长反应，但α 9诱导的再生长仅限于损伤部位。整联蛋白受体的活化状态也是关键的，因为无活性的整联蛋白不诱导生长。脊髓损伤部位的髓鞘碎片和硫酸软骨素蛋白聚糖水平增加，并且两者都已被证明可抑制整联蛋白，进一步阻碍修复。这种作用可以通过使用称为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，但需要进一步研究这种相互作用以优化和最大化生长反应以诱导显著的再生。该博士项目将提供细胞测定和神经科学（安德鲁斯）以及生物物理学和生物化学（古尔特）方面的尖端多学科培训，以测试塔林-金德林-整合素轴以可调节的方式调节神经突生长的假设，并且该途径的激活可能会实现治疗脊髓损伤的新方法。