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: 8945775
• 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/8945775
• 关键词: Apoptotic; Autophagocytosis; Brain; Brain Injuries; Cell Nucleus; Cells; Cessation of life; Cytoplasm; Data; Development; Disease; Encephalitis; Endosomes; Epilepsy; Epileptogenesis; Eukaryotic Cell; Figs - dietary; Genomics; Goals; Hippocampus (Brain); IRF3 gene; Immune; Immune response; Inflammation; Inflammatory; Inflammatory Response; Interferon Type I; Interferons; Knockout Mice; Lead; Location; Mediating; Microglia; Modeling; Mus; Nerve Degeneration; Neuronal Injury; Neurons; 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; human FRAP1 protein; immune activation; in vivo; injury and repair; mouse model; nervous system disorder; 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（由适用提供）：癫痫是一种毁灭性的神经系统疾病，几乎无法治愈，需要连续存在治疗。此外，大约三分之一的癫痫患者对可用药物难治性。因此，需要理解癫痫发生的迫切需要，这是将正常脑转化为癫痫大脑的病理过程。在获得的癫痫发生中，癫痫生成通常在脑损伤后开始开始，并且越来越多地被认为涉及脑部感染。小胶质细胞是大脑中的主要免疫力。然而，小胶质细胞在癫痫发生中的作用仍然很少了解。我们的初步研究表明，双链DNA（DSDNA）可以引发小胶质细胞中强大的先天免疫反应。此外，我们发现自噬途径中的激酶ULK1失活会促进对DSDNA的先天免疫反应。鉴于神经退行性与在大多数获得的癫痫发生中的早期癫痫发生密切相关，并且在癫痫患者的大脑中也观察到：1）从死神经元中释放出来的dsDNA可能是触发的触发因素，它会引起微胶质细胞中的先天性免疫响应，从而促进癫痫发生； 2）ULK1是终止先天免疫响应以防止过量炎症过程的关键调节器。在这里，我们建议描述ULK1从退化神经元中调节小胶质细胞对DsDNA的先天免疫反应的途径。我们还将研究ULK1失活对小胶质细胞中先天免疫激素的影响和毛果果小鼠模型中的癫痫发生的影响。最后，我们将采用最近开发的化学发生策略来探测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，以防止小胶质细胞中的炎症过多，从而最大程度地减少了癫痫发作。