TRPV1通过小胶质细胞激活介导发作性疾病的机制研究

Microglia-mediated neural immune inflammatory plays an important role in occurrence, development and prognosis of seizures, which is key for the prognosis and treatment of seizures; Regulation of ion channel activation is quite important to microglia. TGF-β is essential for the survival and activation of microglia and TGF-β1 can activate TRPV1 currents. Meanwhile TRPV1 channels abundant expressed on microglia. Our previous study found that, TRPV1 promotes repetitive febrile seizures by pro-inflammatory cytokines in immature brain and also enhance pro-inflammatory cytokines in microglial cell line BV2. Blocking TLR-4 and HMGB-1 signaling pathway inhibits KA-induced seizures. The pathway of TRPV1 participate the activation of microglia, immune activation and inflammation leading to the occurrence and maintain of seizures has not been elucidated. This project will study role of TRPV1 in the microglia-mediated neuro-inflammatory network disorder via TRPV1 knockout mice. To study microglia activation, proliferation and signaling pathways on febrile seizures and convulsions of hypoxic-ischemic disease animal model, and also the effect of TRPV1 activation on neurons and blood-brain barrier function. To explore whether TRPV1 activation via targeting TGF-β inhibition to activate microglia-mediated immunity downstream signals, and further to aggravate seizures under blood-brain barrier damage, thus providing theoretical and experimental basis for the treatment and prevention of the onset of seizure diseases.

小胶质细胞(MG)介导的神经免疫炎症对小儿惊厥发作意义重大,是治疗及改善预后关键.离子通道可调控MG活化,TGF-β对MG生存活化至关重要.TGF-β1激活TRPV1电流,而MG上TRPV1表达丰富.我们前期发现,TRPV1激活促进反复热性惊厥海马皮层及MG株BV2中促炎因子显著增高.阻断下游信号TLR-4及HMGB-1途径抑制惊厥发作.TRPV1如何参与活化MG,激活免疫炎症导致惊厥的发生及维持机制尚未阐明.本项目围绕TRPV1,研究小儿发作性疾病中MG介导的神经免疫网络异常.以TRPV1-KO鼠为工具,以临床最常见小儿热性惊厥与缺氧缺血性惊厥为疾病模型代表,观察病理状态下原代培养MG活化增殖信号通路及TRPV1激活致神经元和BBB功能结构改变,探讨TRPV1通过靶向抑制TGF-β激活MG,介导下游免疫信号,并在BBBD下加重惊厥发作机制,对发作性疾病的治疗与预防提供理论及实验依据.

胶质细胞介导的神经炎症对小儿癫痫发作意义重大，是治疗的潜在靶点。离子通道的激活或异常表达调控病理状态下胶质细胞的激活及炎症反应。根据前期的工作基础，我们着眼于TRPV1在两种诱因（缺血缺氧与反复热）下的惊厥发生中的作用。.小胶质细胞TRPV1通道，促进小胶质细胞增殖、活化和迁移，加剧神经炎症反应，并生成和释放TGF-β1。一方面，TRPV1通过与TLR4相互作用，协同抑制TGF-β1介导的小胶质细胞M2型极化，加剧神经炎症反应，促进惊厥发作。另一方面，大量的TGF-β1直接敏化神经元TRPV1，增加神经元兴奋性，促进惊厥发作。.星型胶质细胞TRPV1通道，促进星型胶质细胞激活和迁移，加重神经炎症反应，并合成和释放IL-1β。病理状态下，TRPV1向膜上迁移，促进星型胶质细胞向A1亚型转变，加重炎症反应，促进惊厥发生。另一方面，TRPV1促进星型胶质细胞NLRP3炎症小体的形成，星型胶质细胞分泌的炎性介质（IL-1β）直接敏化神经元，增加神经元兴奋性，促进惊厥发作。.研究意义在于在不同病理状态下的癫痫中，TRPV1通过胶质细胞促进神经炎症的爆发诱导神经元异常兴奋性（胶质细胞-神经元轴）。为治疗癫痫提供了新的治疗靶点，TRPV1在中枢神经系统中的作用更加清晰。