Evaluating the Role of Inflammation in Neonatal Epileptogenesis

评估炎症在新生儿癫痫发生中的作用

• 批准号: 10055785
• 负责人: Adam Lawrence Numis
• 金额: $ 20.02万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055785
• 关键词: 2 year old; Acute; Acute Brain Injuries; Affect; Age-Months; Animal Model; Anti-Inflammatory Agents; Astrocytes; Award; Bioinformatics; Blood; Blood specimen; Brain; Brain Injuries; Cerebral Palsy; Child; Childhood; Chronic; Data; Development; Diagnosis; Disease Marker; Enrollment; Epilepsy; Epileptogenesis; Family; Frequencies; Future; Gene Expression; Gene Expression Profiling; Genetic Transcription; Goals; Hour; Immunologics; Immunology; Individual; Infant; Inflammation; Inflammatory; Infrastructure; Injury; Intellectual functioning disability; Interleukin-1 beta; Interleukin-6; Investigation; Longterm Follow-up; Medical; Mentors; Mentorship; Methodology; Methods; MicroRNAs; Microglia; Molecular; Neonatal; Nested Case-Control Study; Neurologic; Neurologic Dysfunctions; Neurologic Signs; Newborn Infant; Pathway interactions; Patients; Pattern; Pediatric cohort; Pharmacotherapy; Plasma; Population; Populations at Risk; Process; Prospective cohort; Prospective cohort study; Provider; Recurrence; Registries; Research; Research Personnel; Resistance; Risk; Risk Factors; Rodent Model; Role; Seizures; Severities; Severity of illness; Small RNA; Stroke; TNF gene; Therapeutic; Time; Training; Translations; Traumatic Brain Injury; United States; Untranslated RNA; Up-Regulation; Vulnerable Populations; acquired epilepsy; career; case control; cohort; common symptom; cytokine; design; high risk; individual patient; injured; insight; large datasets; neonatal patient; neonatal period; neonatal seizure; neonate; neurodevelopment; neuroinflammation; new therapeutic target; novel therapeutics; prevent; sex; skills; treatment optimization

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.

项目概要 癫痫发作是新生儿期神经功能障碍的常见症状，影响超过 16,000 美国每年新生儿数量。超过 25% 的患有急性症状性癫痫发作的新生儿是在术后发生的。 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 患有 PNE 风险最高的患者并了解早期癫痫发作增加倾向的机制 针对复发性癫痫发作，希望在这一人群中找到新的治疗靶点。有越来越多 神经炎症在癫痫发展中的作用的证据。细胞因子和 micro-RNA 水平 (miRNA) 可作为疾病严重程度的标志物，并与动物的癫痫发生有关 模型。研究血浆细胞因子或 miRNA 水平与获得性癫痫之间的关系 然而，尚未在儿科人群中进行过研究。我们的长期目标是确定那些处于最高水平的人 发展 PNE 的风险并探索可能最终预防急性脑后癫痫的新疗法 该人群中的伤害。我们的目标是评估新生儿出生后的血浆细胞因子和 miRNA 水平 发作急性症状性癫痫发作并确定其与急性癫痫发作严重程度和 PNE 的关系。这 中心假设是特定促炎分子的增加与急性炎症相关。 症状性癫痫发作的严重程度和 PNE 的后续发展。这项调查将利用现有的 国家联盟，名为新生儿癫痫登记 II (NSR II)，旨在了解新生儿癫痫发作的影响 新生儿癫痫发作后抗癫痫药物治疗对神经发育和 PNE 风险的影响。在 NSRII 内，我们 将创建一项具有巢式病例对照成分的前瞻性队列研究，招募 72 名患有急性 有症状的癫痫发作以及 15 名“对照”受试者。将在出院前和下午 2-4 点采集血液 月龄，然后分析细胞因子和 miRNA 的水平。 24 日评估 PNE 诊断 月龄。细胞因子的表达模式将与急性疾病的存在和严重程度相关 有症状的癫痫发作（目标 1），并对 PNE 的发展进行预测分析（目标 2）。我们将 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 癫痫在高危人群中的发展并优化这些患者的治疗方案 发展为癫痫症。在此奖励期间，我将获得注册管理机构开发、高级 用于管理大数据集的免疫学方法、基因表达谱和生物信息学 - 所有 当我转向独立调查员时，这是必要的。该技能组合与专家相结合 我在这里获得的指导和数据将为未来的 R01 在更大范围内评估这些分子途径提供信息 患有急性症状性癫痫发作的新生儿群体以及有癫痫风险的类似儿科人群 癫痫，包括脑外伤和中风患者。