Aging and Peripheral Nerve Regeneration

描述(申请人提供)：在哺乳动物神经元的发育过程中，局部环境是允许这种生长的，并且存在引导信号，引导神经元指向其特定的目标，共同导致功能神经回路的形成。在成熟的分化神经元中，缺乏内在生长所需的分子机制。然而，周围神经系统(PNS)中轴突的损伤会增加感觉和运动神经元的内在生长，在最佳条件下，会发生再生，并恢复功能。这项建议的目的是研究小鼠三叉神经核再生的速度和程度随年龄的变化，这个课题几乎没有受到关注，特别是在机械水平上，尽管周围神经病和神经损伤在老年人中很常见。这一建议是基于我们的初步数据，该数据表明，小鼠的衰老会减缓再生，这与固有神经元生长的变化无关，但老年动物的雪旺细胞在幼鼠神经损伤后有差异的转录变化。现在的目标将是机械地询问衰老的雪旺细胞的功能，并确定哪些年龄相关的途径会影响周围神经的再生。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，这是开发潜在的患者治疗干预措施的第一步。 与公共卫生相关：与中枢神经系统的轴突不同，三叉神经节的轴突在受伤后可以再生。尽管人们已经意识到三叉神经节轴突的再生能力随着年龄的增长而下降，但导致这种情况的机制尚未阐明，因此我这个项目的目标是确定衰老是否会导致老年动物神经损伤后雪旺细胞室内功能障碍，从而导致功能恢复下降。我的目标是确定哪些特定的雪旺细胞通路会随着年龄的增长而改变，以及这些通路如何影响外周再生。

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. PUBLIC HEALTH RELEVANCE: Axons of the PNS, unlike those of the CNS, can regenerate after injury. Although it has been appreciated for some time that the ability of axons of the PNS to regenerate decreases as a function of age, the mechanisms responsible for this have yet to be elucidated, so my goal for this project is to determine whether aging produces dysfunction within the Schwann cell compartment, which leads to decreased functional recovery after nerve injury in old animals. My goal is to determine what specific Schwann cell pathways are altered with age, and how these affect peripheral regeneration.