NGF/TrkA信号转导通路在神经病理性疼痛的发生中起重要作用。驱动蛋白家族成员KIF1A将TrkA从神经元胞体转运至神经末梢，kif1a基因剔除小鼠表型为痛觉缺失而且NGF/TrkA信号转导减弱，表明KIF1A是NGF/TrkA信号转导通路的一环。我们发现外源性NGF使KIF1A蛋白表达增多，拮抗TrkA作用则KIF1A蛋白表达减少，提示NGF通过TrkA增加KIF1A蛋白表达。表观遗传学研究表明DNA启动子CpG位点去甲基化可使相关基因高表达并且参与痛觉超敏，我们预实验证实神经病理性疼痛模型小鼠的基因组DNA整体甲基化水平明显降低，因而我们假设TrkA使KIF1A蛋白表达增多的机制是活化的pTrkA促进kif1a基因启动子CpG序列去甲基化。本课题拟以表观遗传学为切入点，探索pTrkA调控kif1a基因启动子DNA去甲基化及转录活性的分子机制，为神经病理性疼痛的治疗寻找新靶点。

The nerve growth factor/tropomyosin receptor kinase A (NGF/TrkA) signaling pathway plays an important role in the pathogenesis of neuropathic pain. We have previously found that kinesin superfamily member 1A-KIF1A is a major axonal transport motor protein that is involved in delivering TrkA from cell body to the nerve ending. The depletion of kifla gene can result in deficiency in the pain sensation and in an attenuated NGF/TrkA signaling indicating a membership of KIF1A in the NGF/TrkA signaling pathway. NGF treatment increased the expression of KIF1A at the protein level, whereas the expression level of KIF1A was decreased by means of TrkA antagonist, highlighting the possibility that NGF increases the expression of KIF1A via TrkA. Epigenetically, DNA demethylation in CpG sequence causes the high expression of related genes. It is reported that demethylation regulation is implicated in pain hypersensitivity, our preliminary results showed that the genomic DNA methylation was significantly down-regulated in sciatic nerve chronic constriction injury (CCI) mice. In this project, we hypothesize that the increased levels of KIF1A by NGF treatment may associate with phospho-TrkA dependent DNA demethylation in CpG sequence of kif1a promoter and may produce pain. However, it remains unclear how phospho-TrkA affects DNA demethylation of kif1a promoter and transcription. Therefore, a deeper insight into the molecular mechanism of kif1a DNA demethylation and transcription may yield a new therapeutic target for neuropathic pain.