Is EphA4 the major molecular regulator of axonal regeneration?

每年有相当数量的澳大利亚人受到脊髓损伤的影响。大约一半的脊髓损伤病例会导致四肢瘫痪，上肢和下肢都有不同程度的功能丧失。损伤后脊髓轴突的修复程度有限，这意味着这种瘫痪通常是永久性的。虽然无法行走是一个严重的问题，但手臂和手的有限功能导致丧失独立性，这是造成这一问题巨大的个人、经济和社区成本的一个主要因素，估计每年给澳大利亚社区造成2亿美元的损失。近年来，对中枢神经系统修复问题的先进解剖学和分子方法为神经损伤的神经元和神经胶质反应提供了很好的见解，神经损伤似乎决定了神经再生的成败。我们的初步数据表明，受体酪氨酸激酶EphA4是脊髓损伤后神经再生的有效抑制因子，在发育中的神经系统中对轴突通路至关重要。在这个项目中，我们将确定EphA4发挥抑制作用的机制，并研究中和EphA4信号对神经再生的影响。成功实现这一结果将导致开发一种治疗性干预措施，我们将在小鼠模型上进行测试。

Spinal cord injury affects a substantial number of Australians each year. Around half the number of spinal cord injury cases result in quadriplegia, with loss of function to a varying degree in the upper as well as the lower limbs. The limited degree of repair of spinal axons following injury means that such paralysis is usually permanent. Although the inability to walk is a serious issue, the limited function of the arms and hands results in a loss of independence which is a major factor contribuing to the enormous personal, financial, and community costs of this problem, estimated to cost the Australian community $200 million a year. In recent years advanced anatomical and molecular approaches to the problem of repair of the central nervous system have provided great insights into the neuronal and glial reactions to neural damage that appear to govern the success or failure of neural regeneration. Our preliminary data indicate that a receptor tyrosine kinase, EphA4, which is important for axonal pathfinding in the developing nervous system, is a potent inhibitor of neural regeneration following spinal cord injury. In this project we will determine the mechanisms by which EphA4 exerts its inhibitory effects, and examine the effect of neutralizing EphA4 signalling on neural regeneration. Success in achieving this result will lead to the development of a therapeutic intervention that we will test in mouse models.