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: 10524764
• 负责人: Adam Lawrence Numis
• 金额: $ 22.83万
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10524764
• 关键词: 2 year old; Acute; Acute Brain Injuries; Affect; Age; Age Months; Animal Model; Anti-Inflammatory Agents; Anticonvulsants; 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; 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; Stratification Factors; 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 period; neonatal seizure; neonate; neurodevelopment; neuroinflammation; new therapeutic target; novel therapeutics; participant enrollment; 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.

项目摘要 癫痫发作是新生儿期神经功能障碍的常见症状， 美国每年的新生儿。超过25%的急性症状性癫痫发作的新生儿发生后， 新生儿癫痫（PNE），通常对药物治疗有抵抗力。迫切需要查明 PNE风险最高的患者，并了解早期癫痫发作增加PNE倾向的机制。 用于复发性癫痫，希望在这一人群中找到新的治疗靶点。人们日益 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，并与动物癫痫的发生有关 模型血浆细胞因子或miRNA水平与获得性癫痫关系的研究 然而，在儿科人群中尚未进行。我们的长期目标是找出那些 风险发展PNE和探索新的治疗方法，可能最终预防癫痫后急性脑 在这个人群中受伤。我们的目的是评估新生儿- 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。的 中心假设是特定促炎分子的增加与急性炎症反应相关。 症状性癫痫发作的严重程度和随后发生PNE。这项调查将利用现有的 国家联合会，题为新生儿癫痫登记II（NSR II），旨在了解 抗惊厥药物治疗对新生儿惊厥后神经发育及PNE的危险性。在NSRII中，我们 将创建一项前瞻性队列研究，包括巢式病例对照部分，招募72名患有急性 症状性癫痫发作以及15名"对照"受试者。将在出院前和2 - 4时采集血液 月龄，然后分析细胞因子和miRNA的水平。PNE的诊断评估在24 月龄。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），并对PNE的发展进行预测分析（目标2）。我们将 用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，并优化这些患者的治疗方案 发展成癫痫。在此期间，我将获得注册表开发，高级 用于管理大型数据集的免疫学方法、基因表达谱分析和生物信息学-全部 这是我向独立调查员转型的必要条件这套技能与专家相结合 指导和我在这里获得的数据将为未来的R01提供信息，在更大的范围内评估这些分子途径。 急性症状性癫痫发作的新生儿人群，以及类似的儿科队列中存在以下风险： 癫痫，包括创伤性脑损伤和中风。

项目成果

Comparison of multiplex cytokine assays in a pediatric cohort with epilepsy.

• DOI: 10.1016/j.heliyon.2021.e06445
• 发表时间: 2021-03
• 期刊: Heliyon
• 影响因子: 4
• 作者: Numis AL;Fox CH;Lowenstein DJ;Norris PJ;Di Germanio C
• 通讯作者: Di Germanio C

Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures.

• DOI: 10.1038/s41390-021-01509-3
• 发表时间: 2022-03
• 期刊: PEDIATRIC RESEARCH
• 影响因子: 3.6
• 作者: Numis, Adam L.;da Gente, Gilberto;Sherr, Elliott H.;Glass, Hannah C.
• 通讯作者: Glass, Hannah C.

Neonatal Seizure Management: What Is Timely Treatment and Does It Influence Neurodevelopment?

新生儿癫痫发作管理：什么是及时治疗？它是否会影响神经发育？

• DOI: 10.1016/j.jpeds.2021.12.004
• 发表时间: 2022
• 期刊: The Journal of pediatrics
• 作者: Numis,AdamL;Shellhaas,RenéeA
• 通讯作者: Shellhaas,RenéeA

Risk of seizures in neonates with hypoxic-ischemic encephalopathy receiving hypothermia plus erythropoietin or placebo.

• DOI: 10.1038/s41390-022-02398-w
• 发表时间: 2023-07
• 期刊: PEDIATRIC RESEARCH
• 影响因子: 3.6
• 作者: Glass, Hannah C.;Wusthoff, Courtney J.;Comstock, Bryan A.;Numis, Adam L.;Gonzalez, Fernando F.;Maitre, Nathalie;Massey, Shavonne L.;Mayock, Dennis E.;Mietzsch, Ulrike;Natarajan, Niranjana;Sokol, Gregory M.;Bonifacio, Sonia L.;Van Meurs, Krisa P.;Thomas, Cameron;Ahmad, Kaashif A.;Heagerty, Patrick J.;Juul, Sandra E.;Wu, Yvonne W.
• 通讯作者: Wu, Yvonne W.

Safety of Early Discontinuation of Antiseizure Medication After Acute Symptomatic Neonatal Seizures.

• DOI: 10.1001/jamaneurol.2021.1437
• 发表时间: 2021-07-01
• 期刊: JAMA neurology
• 影响因子: 29
• 作者: Glass HC;Soul JS;Chang T;Wusthoff CJ;Chu CJ;Massey SL;Abend NS;Lemmon M;Thomas C;Numis AL;Guillet R;Sturza J;McNamara NA;Rogers EE;Franck LS;McCulloch CE;Shellhaas RA
• 通讯作者: Shellhaas RA