凝血酶敏感蛋白-4在低级别胶质瘤相关癫痫发生机制中的作用研究

Seizure is one of the most common symptoms of low-grade gliomas (LGGs), which seriously affects the quality of life and prognosis of patients. It is well known that the structural remodeling and dysfunction of the chemical synapse play a key role in the development of LGGs, but the mechanism has not been elucidated. Recent studies have found that thrombospondin-4 (TSP-4) plays a role in the regulation of synaptogenesis in the peripheral and spinal cord. Our previous study found that the expression of TSP-4 in the LGGs of peritumoral epileptogenic focus, suggesting that TSP-4 was closely related to the incidence of LGGs-related epilepsy. Thus, we hypothesized that TSP-4 released by LGGs cells mediated aberrant synaptogenesis may be a potential mechanism of LGGs-related epileptogenesis. This project is intended to use LGGs clinical tissue samples and LGGs animal model for the aims as follow: the location of TSP-4 in LGGs tissues; the regulation effect of TSP-4 in synaptogenesis , synaptic function and epileptiform discharge in the epileptogenic foci of LGGs; Through the study of this project, we hope provide the theoretical evidence for the research and development of the new strategy of clinical treatment of LGGs-related epilepsy.

癫痫是低级别胶质瘤（LGGs）最常见症状之一，严重影响患者生活质量和预后。目前已知，化学突触的结构重塑和功能异常在LGGs癫痫发生过程中发挥关键作用，但其机制尚未阐明。最新研究发现，凝血酶敏感蛋白-4（TSP-4）在外周和脊髓中具有调节突触发生的生物学作用。我们前期研究发现，TSP-4在LGGs瘤周致痫灶中表达上调，提示TSP-4与LGGs癫痫发生密切相关。据此，我们推测：LGGs肿瘤细胞来源的TSP-4介导异常突触发生可能是LGGs癫痫发生的潜在机制。本项目拟以LGGs临床组织样本、颅内转移瘤动物模型为对象，研究：①TSP-4在LGGs的组织细胞来源；②TSP-4对LGGs致痫灶突触发生和突触功能的调控作用及癫痫样放电的影响；通过该项目研究，为LGGs临床治疗新策略的研发奠定理论基础。

临床数据显示，75%以上的低级别胶质瘤（LGG）患者合并癫痫发作，严重影响患者生活质量及预后。目前已知，化学突触的结构重塑和功能异常在多种癫痫发生过程中发挥关键作用，但在LGG相关癫痫的发生机制尚未阐明。本项目以LGG临床组织样本、C6胶质瘤细胞移植模型为研究对象，综合利用形态学、分子生物学、基因组学、皮层脑电监测等技术，证实LGG胶质瘤细胞来源的TSP2促进肿瘤临近皮层内的兴奋性突触形成，引起瘤周皮层内兴奋性突触及树突棘密度上调、化学性突触的超显微结构的改变，但对抑制性突触的密度影响不大，进而导致瘤周皮层癫痫样放电的发生。进一步的研究证实，TSP2可能通过其受体信号通路α2δ1/Rac1调节瘤周兴奋性突触结构重塑的过程，TSP2/α2δ1拮抗剂加巴喷丁（GBP）可部分阻断上述过程。然而，通过GBP阻断TSP2介导的瘤周兴奋性突触发生过程是否对LGG的生物学进展及肿瘤预后是否有影响，还有待进一步的研究。综合上述，通过该项目的研究，初步揭示了胶质瘤细胞来源的TSP2通过促进瘤周组织中兴奋性突触发生、调节瘤周皮层神经环路的重塑，进而介导瘤周皮层癫痫样放电的发生机制，为胶质瘤相关癫痫的发生机制研究提供了新思路，为后续的药物研发等研究提供了理论依据。