Evaluating the Role of Inflammation in Neonatal Epileptogenesis

评估炎症在新生儿癫痫发生中的作用

基本信息

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
项目类别：
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

项目摘要

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 美国每年有超过 25% 的新生儿出现急性症状性癫痫发作。新生儿癫痫（PNE）通常对药物治疗有抵抗力，因此迫切需要识别这些疾病。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对于复发性癫痫发作，希望在这一人群中找到新的治疗靶点。神经炎症在癫痫发展中作用的证据。 (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研究检查血浆细胞因子或 miRNA 水平与获得性癫痫之间的关系。然而，我们的长期目标是确定最高的儿童群体。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我们的目标是评估新生儿后血浆细胞因子和 miRNA 的水平。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。中心假设是特定促炎分子的增加与急性炎症相关。这项调查将利用现有的 PNE 症状癫痫严重程度和后续发展。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在 NSRII 中，新生儿癫痫发作后的抗癫痫药物治疗对神经发育和 PNE 的风险。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 点至 4 点采集血液。月龄，然后分析细胞因子和 miRNA 的水平，并在 24 岁时评估 PNE 的诊断。月龄时细胞因子的表达模式与急性症状的存在和严重程度相关。我们将针对症状性癫痫发作（目标 1）以及 PNE 的发展进行预测分析（目标 2）。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在此奖励期间，我将获得注册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、基因表达谱和生物信息学——全部当我向独立调查员过渡时，这种技能与专家的结合是必要的。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。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Early changes in pro-inflammatory cytokine levels in neonates with encephalopathy are associated with remote epilepsy.

脑病新生儿促炎细胞因子水平的早期变化与远期癫痫有关。

DOI：
发表时间：
2019
期刊：
影响因子：
3.6
作者：
Numis, Adam L;Foster;Deng, Xutao;Rogers, Elizabeth E;Barkovich, A James;Ferriero, Donna M;Glass, Hannah C
通讯作者：
Glass, Hannah C

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

接受低温加促红细胞生成素或安慰剂的缺氧缺血性脑病新生儿癫痫发作的风险。

DOI：
发表时间：
2023-07
期刊：
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
通讯作者：
Thomas

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

癫痫儿科队列中多重细胞因子测定的比较。

DOI：
发表时间：
2021-03
期刊：
影响因子：
4
作者：
Numis, Adam L;Fox, Christine H;Lowenstein, Daniel J;Norris, Philip J;Di Germanio, Clara
通讯作者：
Di Germanio, Clara

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

急性症状性新生儿癫痫发作后早期停用抗癫痫药物的安全性。

DOI：
发表时间：
2021
期刊：
影响因子：
29
作者：
Glass, Hannah C;Soul, Janet S;Chang, Taeun;Wusthoff, Courtney J;Chu, Catherine J;Massey, Shavonne L;Abend, Nicholas S;Lemmon, Monica;Thomas, Cameron;Numis, Adam L;Guillet, Ronnie;Sturza, Julie;McNamara, Nancy A;Rogers, Elizabeth E;Franck, Li
通讯作者：
Franck, Li

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？