Evaluating the Role of Inflammation in Neonatal Epileptogenesis

项目总结 癫痫发作是新生儿期神经功能障碍的常见症状，影响到16,000多人 每年在美国出生的新生儿。超过25%的有急性症状性癫痫的新生儿在 新生儿癫痫(PNE)，通常对药物治疗有抵抗力。迫切需要确定这些 PNE风险最高的患者并了解早期癫痫发作增加倾向的机制 对于反复发作的患者，希望在这一人群中确定新的治疗靶点。有越来越多的 神经炎症在癫痫发生发展中作用的证据。细胞因子和微核糖核酸水平 (MiRNA)可作为疾病严重程度的标志，并与动物癫痫的发生有关 模特们。血浆细胞因子或miRNA水平与获得性癫痫关系的研究 然而，在儿科人群中，还没有进行过。我们的长期目标是找出那些最高层的人 发展PNE的风险和探索可能最终预防急性脑后癫痫的新疗法 在这一人群中的伤害。我们的目标是评估新生儿出生后血浆细胞因子和miRNA水平。 发作急性症状性癫痫，并确定其与急性癫痫发作严重程度和PNE的关系。这个 中心假设是，特定的促炎分子的增加将与急性 症状性癫痫的严重程度和随后的PNE的发展。这项调查将利用现有的 国家联合会，名为新生儿扣押登记处II(NSR II)，旨在了解 抗癫痫药物治疗对新生儿癫痫发作后神经发育和PNE的影响。在NSRII中，我们 将创建一项包含嵌套病例对照成分的前瞻性队列研究，纳入72名患有急性呼吸道感染的新生儿 有症状的癫痫发作以及15名“对照”受试者。出院前和出院后2-4点采血 然后分析细胞因子和miRNA的水平。PNE诊断在24岁时评估 几个月大的孩子。细胞因子的表达模式将与急性胰腺炎的存在和严重程度相关 症状性癫痫发作(目标1)，以及对PNE的发展进行预测分析(目标2)。我们会 对miRNA水平进行类似的分析(目标3)。作为一名儿科癫痫专家，我的职业目标是预防 高危人群中癫痫的发展及患者的最佳治疗方案 患上癫痫。在此授奖期间，我将获得注册表开发方面的专业知识，高级 用于管理大数据集的免疫学方法、基因表达图谱和生物信息学-所有 在我向独立调查员过渡的过程中，这是必要的。此技能集与专家 我在这里获得的指导和数据将为未来的R01提供信息，以更大的 有急性症状性癫痫发作的新生儿以及类似的儿童队列中患急性癫痫的风险 癫痫包括创伤性脑损伤和中风。

PROJECT SUMMARY Seizures are a common symptom of neurologic dysfunction in the neonatal period, affecting more than 16,000 newborns in the United States per year. Over 25% of neonates with acute symptomatic seizures develop post- neonatal epilepsy (PNE), which is often resistant to medical therapies. There is a critical need to identify those patients most at risk for PNE and understand the mechanisms by which early seizures increase the propensity for recurrent seizures, in hopes of identifying novel therapeutic targets in this population. There is increasing evidence for the role of neuro-inflammation in the development of epilepsy. Levels of cytokines and micro-RNA (miRNA) may serve as markers of disease severity and have been implicated in epileptogenesis in animal models. Studies examining the relationship between plasma cytokine or miRNA levels with acquired epilepsy in pediatric populations however, have not been performed. Our long-term goal is to identify those at highest risk of developing PNE and explore novel therapeutics that may ultimately prevent epilepsy after acute brain injury in this population. Our objective here is to evaluate plasma cytokine and miRNA levels after neonatal- onset acute symptomatic seizures and determine their association with acute seizure severity and PNE. The central hypothesis is that increases in specific pro-inflammatory molecules will be associated with acute symptomatic seizure severity and subsequent development of PNE. This investigation will leverage an existing national consortium, entitled the Neonatal Seizure Registry II (NSR II) which aims to understand the effect of anti-seizure drug therapy after neonatal seizures on the risk of neurodevelopment and PNE. Within NSRII, we will create a prospective cohort study with a nested case-control component, enrolling 72 neonates with acute symptomatic seizures as well as 15 `control' subjects. Blood will be collected prior to discharge and at 2-4 months of age, then analyzed for levels of cytokines and miRNA. The diagnosis of PNE assessed at 24 months of age. Expression patterns of cytokines will be correlated with presence and severity of acute symptomatic seizures (Aim 1), and prediction analyses performed for development of PNE (Aim 2). We will conduct similar analyses with miRNA levels (Aim 3). As a pediatric epileptologist, my career goal is to prevent the development of epilepsy in at-risk populations and optimize treatment regiments in those patients who do develop epilepsy. During this award period, I will acquire expertise in registry development, advanced immunologic methods, gene expression profiling, and bioinformatics for management of large data sets – all necessary as I transition towards an independent investigator. This skill-set, in combination with expert mentoring and the data I acquire here will inform a future R01 evaluating these molecular pathways in a larger population of neonates with acute symptomatic seizures, as well as in similar pediatric cohorts at-risk for epilepsy including those with traumatic brain injury and stroke.