Regulation of cutaneous axon regeneration by wound derived H2O2

项目总结(见说明)： 损伤后皮肤感觉神经轴突的再生能力对于恢复组织功能至关重要。尽管它的重要性和过去的许多研究努力，但损伤后皮肤轴突再生的机制仍然难以捉摸。我们之前已经发现，小分子活性氧过氧化氢(H_2O_2)是刺激皮肤轴突生长的关键调节分子。在历史上，当存在高浓度的过氧化氢时，它一直被视为一种破坏细胞的分子 在牢房里。然而，最近的研究表明，低浓度、无毒的过氧化氢对许多细胞功能的调节是重要的。这是通过氧化信号蛋白中对氧化还原敏感的半胱氨酸残基来实现的，最明显的是激酶、磷酸酶和转录因子，这改变了它们的结构和功能。由于过氧化氢信号转导的研究领域相对较新，对其在组织修复过程中的信号特性的了解才刚刚开始。这项建议的意义在于，它将阐明损伤诱导的过氧化氢刺激皮肤轴突再生的机制。从这项研究中获得的见解将有助于开发因疾病或创伤而受损的轴突的治疗方法。我们的方法是结合体内成像和miRNAs和mRNAs的平行深度测序来分析躯体感觉神经元中对刺激轴突再生至关重要的过氧化氢反应遗传网络。

PROJECT SUMMARY (See instructions): The ability to regenerate cutaneous sensory axons in response to injury is crucial for restoring tissue function. Despite its importance and many research efforts in the past, the mechanisms for cutaneous axon regeneration following injury have remained elusive. We have previously discovered that the small reactive oxygen species hydrogen peroxide (H2O2) is a key regulatory molecule for stimulating cutaneous axon growth. Historically, H2O2 has been seen as a cell-damaging molecule, when present at high concentrations in cells. Recent work however, demonstrates that low, non-toxic concentrations of H2O2 are important for regulation of many cellular functions. This is achieved by the oxidation of redox-sensitive cysteine residues in signaling proteins, most notably of kinases, phosphatases, and transcription factors, which alters their structure and function. As the research field of H2O2 signaling is relatively new, insight into its signaling properties during tissue repair is only beginning to emerge. The significance of this proposal is that it will elucidate mechanisms utilized by injury-induced H2O2 that stimulate cutaneous axon regeneration. The insight gained from this research will aid in the development of treatments for damaged axons due to disease or trauma. Our approach is to combine in vivo imaging and parallel deep sequencing of miRNAs and mRNAs to analyze H2O2 responsive genetic networks in somatosensory neurons that are essential for stimulating axon regeneration.