Understanding the role of microglia on epileptogenesis

 描述(由申请人提供)：癫痫是一种毁灭性的神经疾病，几乎无法治愈，需要持续的治疗。此外，约三分之一的癫痫患者对可用的药物无效。因此，迫切需要了解癫痫的发生，即将正常大脑转变为癫痫大脑的病理过程。在获得性癫痫中，癫痫的发生通常始于脑损伤后，并越来越多地被认为与脑部炎症有关。小胶质细胞是大脑中的主要免疫细胞。然而，小胶质细胞在癫痫发生中的作用仍然知之甚少。我们的初步研究表明，双链DNA(DsDNA)可以在小胶质细胞中引发强大的先天免疫反应。此外，我们还发现，自噬途径中的一种激酶ULK1的失活促进了对dsDNA的先天免疫反应。鉴于在大多数获得性癫痫模型中，神经退行性变与癫痫的早期发病密切相关，并且在癫痫患者的大脑中也观察到了这种情况，我们推测：1)死亡神经元释放的dsDNA可能是触发小胶质细胞的先天免疫反应的触发因素，进而促进癫痫的发生；2)ULK1是参与终止先天免疫反应以防止过度炎症过程的关键调节因子。在这里，我们建议描绘ULK1调节小胶质细胞对变性神经元dsDNA的先天免疫反应的途径。我们还将在匹罗卡品小鼠模型中检测ULK1失活对小胶质细胞天然免疫反应和癫痫发生的影响。最后，我们将使用最近开发的化学发生策略来探索小胶质细胞在癫痫发生中的作用。这项研究的结果可能导致新的策略，以防止小胶质细胞过度炎症，从而最大限度地减少癫痫的影响。

 DESCRIPTION (provided by applicant): Epilepsy is a devastating neurological disorder that is nearly incurable, requiring the continuous presence of therapeutics. Moreover, about one-third of patients with epilepsy are refractory to available medications. Therefore, there is a pressing need to understand epileptogenesis, the pathological process that transforms a normal brain into an epileptic brain. In acquired epilepsy, epileptogenesis typically begins following brain injury, and is increasingly recognized to involve brain inflammation. Microglia are the primary immune cells in the brain. However, the role of microglia in epileptogenesis remains poorly understood. Our preliminary study revealed that double-stranded DNA (dsDNA) can trigger a robust innate immune response in microglia. Moreover, we found that inactivation of ULK1, a kinase in the autophagy pathway, promotes the innate immune response to dsDNA. Given that neurodegeneration is strongly associated with an early onset of epileptogenesis in most acquired epilepsy models and is also observed in the brains of epileptic patients, we postulated: 1) dsDNA released from dead neurons could be the trigger that induces the innate immune response in microglia, which in turn promotes epileptogenesis; and 2) ULK1 is a key regulator involved in terminating the innate immune response to prevent an excessive inflammatory process. Here we propose to delineate the pathway by which ULK1 regulates the innate immune response of microglia to dsDNA from degenerated neurons. We will also examine the effect of inactivation of ULK1 on the innate immune response in microglia and epileptogenesis in the pilocarpine mouse model. Finally, we will employ a recently developed chemogenetic strategy to probe the role of microglia in epileptogenesis. Results from this study could lead to new strategies to prevent excessive inflammation in microglia, therefore minimizing the epileptogenic effect.