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

中枢神经系统(CNS)和周围神经系统(PNS)的轴突被一种富含脂质的膜--髓鞘包裹着，它绝缘神经纤维，是快速电导所必需的。在中枢神经系统，髓鞘由少突胶质细胞形成，而在三叉神经节，髓鞘由雪旺细胞形成。在受伤的情况下，神经和髓鞘都会退化。由于髓鞘含有抑制轴突再生的分子，因此巨噬细胞清除髓鞘以允许再生是很重要的。许多不同的因素已被证明影响神经损伤后髓鞘的分解和吞噬。最近的研究表明，脂解酶在周围神经损伤后引发髓鞘的分解和清除中起重要作用(Lopez-Vales等人，2008年)。然而，目前还不知道这些酶的水平和激活是如何调节的。这项建议的目的是研究损伤神经释放的细胞因子和形成孔状通道(连接蛋白29或连接蛋白32通道)的分子的作用，这些分子调节离子通道，离子通道可能允许钙到达髓鞘的某些部分，并触发脂解酶的激活。这些研究可能会揭示新的靶点，可以研究如何促进脊髓损伤后髓鞘的快速清除，以促进再生，因为中枢神经系统的髓鞘清除极其缓慢。它们也可能对周围神经的临床疾病有重要的影响。

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.