Aging and Peripheral Nerve Regeneration

描述（申请人提供）：在发育过程中，哺乳动物神经元生长，局部环境允许这种生长，并且存在引导神经元到达其特定靶点的引导线索，共同导致功能性神经回路的形成。在成熟分化的神经元中，不存在内在生长所必需的分子机制。然而，周围神经系统（PNS）中轴突的损伤增加了感觉和运动神经元的内在生长，并且在最佳条件下，发生再生，功能恢复。本提案的目的是研究小鼠PNS随年龄增长的再生速率和程度的变化，这一主题很少受到关注，特别是在机械水平上，尽管周围神经病和神经病变在老年人中很常见。这一建议是基于我们的初步数据，表明小鼠的衰老减缓了再生，这与内在神经元生长的变化无关，但老年动物的许旺细胞在神经损伤后对年轻小鼠有不同的转录改变。现在的目标将是机械地询问老年雪旺细胞的功能，并确定哪些年龄依赖性途径影响周围神经再生。这些数据将为未来的尝试提供基础，看看老年小鼠的再生能力是否可以恢复到年轻小鼠的水平，作为开发患者潜在治疗干预措施的第一步。

DESCRIPTION (provided by applicant): During development mammalian neurons grow, the local environment is permissive for such growth, and guidance cues are present that direct neurons to their specific targets, collectively leading to formation of functional neural circuits.In mature differentiated neurons the molecular machinery necessary for intrinsic growth is absent. However, injury to axons in the peripheral nervous system (PNS) increases intrinsic growth in sensory and motor neurons, and in optimal conditions, regeneration occurs, with restoration of function. The objective of this proposal is to study changes in the rate and extent of regeneration in the PNS with aging in mice, a subject that has received little attention, particularly at a mechanistic level, even though peripheral neuropathies and nerve lesions are common in the elderly. This proposal is based on our preliminary data showing that aging in mice slows regeneration, and that this is not associated with a change in intrinsic neuronal growth but that Schwann cells in old animals have a differential transcriptional alteration after nerve injury to young mice. The aim now will be to mechanistically interrogate aged Schwann cell function and determine what age- dependent pathways affect peripheral nerve regeneration. These data will provide a basis for future attempts to see if regenerative capacity can be restored in aged mice to levels seen in young mice, as a first step towards the development of potential therapeutic interventions in patients.