活动依赖的组蛋白乙酰化在大脑感知与调控神经病理性疼痛中的作用研究

Abundant achievements have been made in the pre-clinical study of the neuropathic pain mechanism, among which only a few have been testified in the clinical study. The exploration of pain perception and modulation in the animal brain could be helpful in the translation of pre-clinical results into clinical use. The acetylation of histone lysine residues, which is involved in the activity-dependent plasticity, may regulate the transcription of pain-related gene and play an important role in the neuropathic pain perception and modulation in the animal brain. In this study, the relationship will be investigated between the transcription of pain-related genes in the anterior cingulate cortex and the histone acetylation surrounding the target genes in the animal model of peripheral nerve injury. A preliminary screen of pain-related genes whose transcription are potentially modulated by the surrounding histone acetylation will be performed. Then a neuron model of activity-dependent plasticity will be constructed to examine the lysine residue sites which modulate distinctive gene transcription. Finally, the effect of site-specific histone acetylation will be tested on the modulation of pain-related gene transcription and on the subsequent neuropathic sense and affective pain. Based on these experiments, the involvement of activity-dependent histone acetylation in the mechanisms of neuropathic pain perception and modulation in the brain will be explored, which would shed light on the problems of the neuropathic pain treatment.

神经病理性疼痛的基础研究领域成果丰富，而其中能够成功进行临床转化的成果很少。探索动物大脑对疼痛的感知与调控机制，可促进该领域研究成果的转化。组蛋白赖氨酸乙酰化是活动依赖的可塑性变化中的重要环节，可能通过调节各类疼痛相关基因转录参与大脑对神经病理性疼痛的感知与调控。本研究首先通过探索外周神经损伤后大脑前扣带皮层疼痛相关基因转录与基因周围组蛋白乙酰化的联系，筛选可能受组蛋白乙酰化调控转录的疼痛基因；其次通过构建活动依赖的组蛋白乙酰化细胞模型寻找并验证基因特异性的组蛋白赖氨酸乙酰化位点；最后在大鼠模型上验证组蛋白特定位点的赖氨酸乙酰化通过调控疼痛相关基因转录对神经病理性疼痛感觉和疼痛情绪变化的调控作用。通过以上研究，探索活动依赖的组蛋白乙酰化参与大脑对神经病理性疼痛感知与调控的作用机制，为神经病理性疼痛的治疗提供新的理论依据。

本研究首先通过探索外周神经损伤后大脑前扣带皮层疼痛相关基因转录与基因周围组蛋白乙酰化的联系，筛选可能受组蛋白乙酰化调控转录的疼痛基因；其次通过构建活动依赖的组蛋白乙酰化细胞模型寻找并验证基因特异性的组蛋白赖氨酸乙酰化位点；最后在大鼠模型上验证组蛋白特定位点的赖氨酸乙酰化通过调控疼痛相关基因转录对神经病理性疼痛感觉和疼痛情绪变化的调控作用。通过以上研究，探索活动依赖的组蛋白乙酰化参与大脑对神经病理性疼痛感知与调控的作用机制，为神经病理性疼痛的治疗提供新的理论依据。