Is EphA4 the major molecular regulator of axonal regeneration?

脊髓损伤每年都会影响大量的澳大利亚人。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。脊髓轴突损伤后修复的程度有限，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，但手臂和手的功能有限导致失去独立性，这是造成这个问题的巨大个人，财务和社区成本的主要因素，估计每年花费澳大利亚社区2亿美元。近年来，对中枢神经系统修复问题的先进的解剖学和分子方法已经为神经元和神经胶质对神经损伤的反应提供了很好的见解，这些反应似乎决定了神经再生的成功或失败。我们的初步数据表明，受体酪氨酸激酶，EphA4，这是重要的轴突在发育中的神经系统中的寻路，是脊髓损伤后的神经再生的有效抑制剂。在这个项目中，我们将确定EphA4发挥其抑制作用的机制，并检查中和EphA4信号对神经再生的影响。成功实现这一结果将导致我们将在小鼠模型中测试的治疗干预的发展。

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.