支链氨基酸代谢障碍抑制己糖激酶1加重神经病理性疼痛的机制研究

The prevalence of neuropathic pain is very high. Since the treatment of neuropathic pain is difficult, researches on mechanisms and therapeutics of neuropathic pain are more than important. After uncovered the role of purinergic receptor in the development of neonatal pain（Molecular Pain，IF3.53，first author）, the idea of what’s the role of branched-chain amino acids (BCAAs) in the development of neuropathic pain came out. This idea based on the observation of clinical relationship between the high prevalence of neuropathic pain and defective BCAAs metabolism in diabetic patients . Models of defective BCAAs metabolism and neuropathic pain triggered by chronic constrictive injury are combined to test the hypothesis that defective BCAAs metabolism sensitizes neuropathic pain. Methods and techniques including 13C-NMR isotope analysis, metabolomics，mitochondria biology and molecular biology are adopted to elucidate the mechanism－defective BCAAs metabolism inhibits uptake and metabolism of glucose, results in dysfunction of mitochondria by reducing expression and translocation to mitochondria of hexokinase 1. Effect of correcting BCAAs metabolism on neuropathic pain therapy is confirmed by enhancing metabolism of BCAAs. Treatment towards bioenergy metabolism of mitochondria may cut off the pathway through which disturbed glucose metabolism results in neuropathic pain. This study may throw light on BCAAs as the new target of neuropathic pain research and provide a unique direction for the specific neuropathic pain therapeutics.

神经病理性疼痛发病率高，难治疗，对其发生机制及治疗的研究极其重要。继申请人发现嘌呤能受体在新生小鼠疼痛中的作用（Molecular Pain，IF3.53，第一作者）后，结合糖尿病患者神经病理性疼痛发生率高且存在支链氨基酸（BCAAs）代谢障的临床发现，拟研究BCAAs代谢障碍与神经病理性疼痛的关系。本课题将采用BCAAs代谢障碍小鼠及神经病理性疼痛模型，结合行为学、13C-NMR同位素分析、代谢组学、线粒体生物学及分子生物学等多种方法和技术，揭示BCAAs代谢障碍与神经病理性疼痛的关系，系统阐明BCAAs代谢障碍通过减少己糖激酶1表达及向线粒体转位，抑制糖代谢、糖摄取并导致线粒体功能障碍，加重神经病理性疼痛；验证促进BCAAs代谢对神经病理性疼痛的治疗作用。这种针对线粒体能量底物代谢的治疗方案有望从源头切断糖代谢造成神经病理性疼痛的路径，为神经病理性疼痛的治疗甚至预防提供新的靶点。