Control mechanisms of degeneration and immune cell regulation after injury of peripheral nerves or spinal cord

中枢神经系统（CNS）和外周神经系统（PNS）的轴突被富含脂质的膜（髓鞘）包裹，髓鞘使神经纤维绝缘，并且对于快速导电性是必不可少的。在CNS中，髓鞘由少突胶质细胞形成，而在PNS中，髓鞘由许旺细胞形成。在受伤的情况下，神经和髓鞘都会退化。由于髓磷脂含有抑制轴突再生的分子，因此髓磷脂被巨噬细胞清除以允许再生是重要的。许多不同的因素已被证明会影响神经损伤后髓鞘的分解和吞噬作用。最近的研究表明，脂解酶在外周神经损伤后触发髓鞘的分解和清除中是重要的（Lopez-Vales et al.，2008年）。然而，目前尚不清楚这些酶的水平和活化是如何调节的。该提案的目的是研究由受损神经释放的细胞因子和形成孔样通道（连接蛋白29或连接蛋白32通道）的分子的作用，所述孔样通道调节离子的通过，这可以允许钙到达髓鞘的某些部分并触发脂解酶的激活。这些研究可以揭示新的靶点，可以研究这些靶点以促进脊髓损伤后髓鞘的快速清除以增强再生，因为髓鞘清除在中枢神经系统中非常缓慢。它们也可能对周围神经的临床疾病具有重要意义。

Axons of the central nervous system (CNS) and peripheral nervous system (PNS) are wrapped by a lipid rich membrane, the myelin, which insulates the nerve fiber, and is essential for rapid electrical conductivity. In the CNS, the myelin sheath is formed by oligodendrocytes, while in the PNS it is formed by Schwann cells. In cases of injury, both the nerve and myelin sheath degenerate. As myelin contains molecules that inhibit axon regeneration, it is important that myelin is cleared by macrophages to allow for regeneration. A number of different factors have been shown to influence breakdown and phagocytosis of myelin after nerve injury. Recent work has shown that lipolytic enzymes are important in triggering breakdown and clearance of myelin after peripheral nerve injury (Lopez-Vales et al., 2008). However, it is currently not known how levels and activation of these enzymes are regulated. The aim of this proposal is to study the role of cytokines that are released by the injured nerve and of molecules that form pore-like channels (connexin 29 or connexin 32 channels) that regulate the passage of ions, which could allow calcium to reach certain parts of the myelin sheath and trigger the activation of the lipolytic enzymes. These studies could reveal new targets that can be studied to promote rapid myelin clearance after spinal cord injury to enhance regeneration, as myelin clearance is extremely slow in the central nervous system. They could also have important implications for clinical disorders of peripheral nerves.