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类型 基础研究 预答辩日期 2017-11-28
开始(开题)日期 2016-05-25 论文结束日期 2017-09-22
地点 东南大学李文正楼北225 论文选题来源 国家自然科学基金项目     论文字数 5.8 (万字)
题目 LIM激酶在慢性疼痛形成中的作用及机制研究
主题词 LIM激酶,丝切蛋白,慢性疼痛,中枢敏化,突触可塑性
摘要 慢性疼痛严重危害人类健康,其发病周期长且难以治愈,全球患病率高达30% - 40%。导致慢性疼痛的关键因素之一是中枢敏化,而中枢敏化的神经生物学基础则是神经元突触功能的改变。目前对中枢敏化介导的慢性疼痛缺乏有效的治疗手段。LIM激酶(LIMKs)是一种丝氨酸 / 苏氨酸激酶,广泛表达于中枢神经系统,主要以丝切蛋白cofilin和环磷腺苷效应元件结合蛋白CREB等下游蛋白为调控底物,介导突触可塑性变化及神经元功能调控。因此,在大脑长时程突触增强和记忆的巩固过程中起到关键的作用。虽然目前已有研究从外周神经系统的角度报道了LIMKs在慢性疼痛调控中的作用,但是LIMKs如何调控中枢敏化的机制仍然有待探索。 在本课题中,我们以LIMKs敲除小鼠为模型,着眼于LIMKs在慢性疼痛形成中的调控作用以及调控机制,利用行为学、生物化学、影像学和电生理等研究方法对这一目标进行了探索。首先,我们发现LIMKs的功能缺失虽然不影响脊髓背角的神经元结构和伤害性疼痛感知,但是会显著抑制慢性疼痛的发生。其次,在保留性神经损伤模型中,我们发现LIMKs的缺失会影响慢性疼痛中兴奋性突触后电流的增强和形成新生突触。并且,我们检测到脊髓中的LIMKs会在神经损伤后出现时程特异性的活化,而在维持阶段则没有明显的活性改变。以此为基础,我们利用LIMKs的抑制剂LIMKi - 3对慢性疼痛发生阶段的LIM激酶活性进行了抑制,发现可以在电生理、生化及行为学水平明显改善保留性神经损伤导致的中枢敏化。最后,我们发现针对术后痛这种有明确起始时间的慢性疼痛,抑制LIMKs的活性也可以起到很好的治疗效果。
英文题目 The Mechanism and Function of LIM-kinase in the Development of Chronic Pain
英文主题词 LIM-Kinase, Chronic pain, Central sensitization, cofilin, Synaptic plasticity
英文摘要 Chronic pain is a prevalent clinical condition and extremely challenging to be managed. About 30%-40% population are affected by chronic pain all over the world. Central sensitization represents a key mechanism mediating chronic pain, a major clinical problem lacking effective treatment options. LIM motif-containing protein kinases (LIMKs), a kind of serine/threonine kinase, are widely expressed in the central nervous system. LIMKs selectively regulate several substrates, e.g. cofilin and cAMP response element-binding protein (CREB), that profoundly affect neural activities, such as synaptogenesis and gene expression, thus being critical in the consolidation of long-term synaptic potentiation and memory consolidation in the brain. Although recent research revealed the function of LIMKs in primary afferent neuron in chronic pain regulation, but the mechanism of LIMK-mediated central sensitization are remain unknown. In this study, using LIMK KO mice as a model, we investigated the functions of LIMKs in chronic pain formation by behavioral study, biochemistry, imaging and electrophysiology. Firstly, we demonstrate that LIMK deficiency significantly impaired the development of multiple forms of chronic pain, but with minimal effects on dorsal horn structure and nociception. Then, mechanistic studies focused on spared nerve injury (SNI) model revealed a pivotal role of LIMKs in the up-regulation of spontaneous excitatory synaptic transmission and synaptogenesis after pain induction. We also found that LIMKs were activated after nerve injury, but returned to basal level during chronic pain maintenance stage. Accordingly, pharmacological inhibition of LIMKs targeting this critical period remarkably attenuated central sensitization in the spinal cord and alleviated pain behaviors. We propose that selectively targeting LIMKs during their activation phase may be utilized as a potential therapeutic strategy for clinical management of chronic pain, especially for chronic pain with predictable onset and development time courses, such as chronic post-surgical pain (PSP). Our findings suggest that LIMKs are important for chronic pain formation, and revealed the mechanism of synaptic plasticity mediated by LIMKs in central sensitization. Base on the critical role of LIMKs in the development of chronic pain, we propose to use LIMKi-3 to inhibit LIMKs activity as a new strategy to prevent chronic pain. LIMKs are a potential target for analgesic drug development.
学术讨论
主办单位时间地点报告人报告主题
东南大学生命科学研究院 2016.12 李文正楼213 寿天德 Stream-preferred modulation of feedback projections from the higher areas to lower areas in the visual cortex
东南大学生命科学研究院 2016.10 李文正楼213 杨翔宇 The function of endogenous Amyloid-β in memory consolidation
东南大学生命科学研究院 2013.05 李文正楼213 时松海 Neocortex development: from neurogenesis to circuit assembly
东南大学生命科学研究院 2014.03 李文正楼213 蒲木明 大脑的可塑性:从突触到认知
东南大学生命科学研究院 2015.04 李文正楼213 王玉田 Critical role of long-term depression in drug addiction
东南大学生命科学研究院 2015.12 李文正楼213 杨翔宇 Alzheimers Disease Research Update
东南大学生命科学研究院 2016.03 李文正楼213 杨翔宇 LIM Motif-Containing Protein Kinases Are Required for Chronic Pain Formation
东南大学生命科学研究院 2016.12 李文正楼213 杨翔宇 Memory consolidation,reconsolidation and forgetting
     
学术会议
会议名称时间地点本人报告本人报告题目
日本神经科学大会 2017.07 日本 千叶 Activation of LIMK1 in hippocampo-cortical circuit is required for spatial memory stabilization
神经再生协同创新中心研究生学术论坛 2015.04 江苏南通 LIM Motif-Containing Protein Kinases Are Required for Chronic Pain Formation
     
代表作
论文名称
Transient inhibition of LIMKs significantly attenuated central sensitization and delayed the develop
 
答辩委员会组成信息
姓名职称导师类别工作单位是否主席备注
李相尧 正高 教授 博导 浙江大学
刘文涛 正高 教授 博导 南京医科大学
曹征宇 正高 教授 博导 中国药科大学
姚红红 正高 教授 博导 东南大学
潘玉峰 正高 教授 博导 东南大学
      
答辩秘书信息
姓名职称工作单位备注
吕卉卉 副高 工程师 东南大学