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.

项目摘要癫痫发作是新生儿时期神经功能障碍的常见症状，影响超过16,000 每年在美国的新生儿。超过25％的新生儿患有急性症状性癫痫发作 - 新生儿癫痫（PNE），通常对医疗疗法有抵抗力。肯定要识别那些患者最有PNE风险的患者，并了解早期癫痫发作的机制对于复发性癫痫发作，希望在该人群中识别新的治疗靶标。有在增加神经炎症在癫痫发展中的作用的证据。细胞因子和微RNA的水平（miRNA）可以用作疾病严重程度的标志，并且在动物的癫痫发生中已隐含型号。研究血浆细胞因子或miRNA水平与获得性癫痫的研究但是，在小儿种群中，尚未进行。我们的长期目标是确定那些处于最高的目标患PNE并探索新型疗法的风险最终可能预防急性大脑后癫痫该人群受伤。我们的目的是评估新生儿后血浆细胞因子和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的关联。中心假设是特定促炎分子的增加将与急性有关有症状的癫痫发作严重程度和随后的PNE发展。这项投资将利用现有的国家财团，题为新生儿癫痫发作登记处II（NSR II），旨在了解关于神经发育和PNE风险的新生儿癫痫发作后的抗塞氏菌药物疗法。在NSRII中，我们将通过嵌套的病例对照组件创建一项前瞻性队列研究，急性招募72个新生儿有症状的癫痫发作以及15个“控制”受试者。出院前和2-4之前将收集血液几个月大，然后分析了细胞因子和miRNA的水平。评估的PNE诊断为24 几个月。细胞因子的表达模式将与急性的存在和严重程度相关有症状的癫痫发作（AIM 1）和用于开发PNE的预测分析（AIM 2）。我们将用miRNA水平进行类似的分析（AIM 3）。作为一名儿科癫痫学家，我的职业目标是防止在高危人群中癫痫的发展，并优化那些患者的治疗方案发展癫痫。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 - 所有当我向独立调查员过渡时，有必要。这种技能与专家结合指导和我在这里获得的数据将告知未来的R01，以评估这些分子途径急性症状性癫痫发作的新生儿，以及类似的小儿同龄人的处于危险中癫痫病，包括脑损伤和中风的癫痫病。

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）

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
影响因子：
0
作者：
Numis,AdamL;Shellhaas,RenéeA
通讯作者：
Shellhaas,RenéeA

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

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.