Understanding the role of microglia on epileptogenesis

了解小胶质细胞在癫痫发生中的作用

• 批准号: 9310361
• 负责人: Yunfei Huang
• 金额: $ 34.56万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9310361
• 关键词: Apoptotic; Autophagocytosis; Brain; Brain Injuries; Cell Nucleus; Cells; Cytoplasm; DNA; Data; Development; Disease; Encephalitis; Endosomes; Epilepsy; Epileptogenesis; Eukaryotic Cell; FRAP1 gene; Genomic DNA; Goals; Hippocampus (Brain); IRF3 gene; Immune; Immune response; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Interferon Type I; Interferons; Knockout Mice; Lead; Location; Mediating; Microglia; Modeling; Mus; Nerve Degeneration; Neuronal Injury; Neurons; Pathologic; Pathologic Processes; Pathway interactions; Patients; Phagocytes; Pharmaceutical Preparations; Phosphotransferases; Pilocarpine; Play; Population; Process; Protein Kinase; Pyramidal Cells; Recurrence; Refractory; Role; Seizures; Signal Transduction; Temporal Lobe Epilepsy; Therapeutic; ds-DNA; early onset; immune activation; in vivo; injury and repair; mouse model; nervous system disorder; neuron loss; neuronal cell body; prevent; public health relevance; receptor; response

 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.

 描述（由申请人提供）：癫痫是一种几乎无法治愈的破坏性神经系统疾病，需要持续治疗。此外，大约三分之一的癫痫患者对现有药物难以治疗。因此，迫切需要了解癫痫发生，将正常大脑转变为癫痫大脑的病理过程。在获得性癫痫中，癫痫发生通常在脑损伤后开始，并且越来越多地被认为涉及脑炎症。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，我们发现ULK 1（自噬途径中的激酶）的失活促进了对dsDNA的先天免疫应答。鉴于在大多数获得性癫痫模型中神经变性与癫痫发生的早期发作密切相关，并且在癫痫患者的脑中也观察到神经变性，我们推测：1）从死亡神经元释放的dsDNA可能是诱导小胶质细胞中的先天免疫反应的触发剂，这反过来又促进癫痫发生;和2）ULK 1是参与终止先天免疫应答以防止过度炎症过程的关键调节剂。在这里，我们建议描绘的途径，ULK 1调节先天免疫反应的小胶质细胞的双链DNA从退化的神经元。我们还将研究ULK 1失活对小胶质细胞先天免疫反应和匹鲁卡品小鼠模型癫痫发生的影响。最后，我们将采用最近开发的化学遗传学策略来探讨小胶质细胞在癫痫发生中的作用。这项研究的结果可能会导致新的策略，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。