Neuronal Seizure Burden versus Cell Death after Neonatal Brain Injury
新生儿脑损伤后神经元癫痫负担与细胞死亡
基本信息
- 批准号:10590729
- 负责人:
- 金额:$ 20.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdvisory CommitteesAnticonvulsantsAwardBenzodiazepinesBiological MarkersBrainBrain InjuriesBumetanideCalciumCell DeathCellsCerebral PalsyCessation of lifeChronicClinicalCorrelation StudiesDataData CorrelationsDetectionDevelopment PlansDevelopmental Delay DisordersDyesElectroencephalographyEpilepsyEpileptogenesisEtiologyExtinctionFluorescenceFoundationsFundingFutureGeneral HospitalsGoalsHypoxiaHypoxic-Ischemic Brain InjuryImageIndividualInfantInjuryInstitutionLaboratoriesLigationLinkMagnetic Resonance ImagingMassachusettsMeasurementMeasuresMentorshipMethodologyMethodsModelingMonitorMusNeonatalNeonatal Brain InjuryNeurological outcomeNeuronsOpsinOutcomePatientsPhenobarbitalPhenytoinPredictive ValueProbabilityProcessProteinsResearchResearch PriorityResolutionResourcesRodent ModelScienceScientistSeizuresSeveritiesTechniquesTechnologyTerm BirthTestingTherapeuticTherapeutic InterventionTimeTrainingTransgenic MiceTransgenic OrganismsUnited States National Institutes of Healthcalcium indicatorcareercareer developmentclinical careclinically relevantdesigneffective therapyexperimental studyimaging modalityimprovedin vivoinnovationinterestmedical schoolsmortalitymouse modelneonatal hypoxic-ischemic brain injuryneonatal miceneonatal seizureneonateneuron lossneuroprotectionneurotoxicitynewborn brain injuryoptogeneticspupreal time modelreal time monitoringred fluorescent proteinsevere injuryskillstargeted treatmenttemporal measurementtherapeutically effectivetreatment strategytwo-photon
项目摘要
PROJECT SUMMARY/ABSTRACT
Hypoxic-ischemic brain injury (HI) complicates 2-6 per 1,000 term births and is associated with significant
mortality and poor neurologic outcomes. HI is also the leading cause of neonatal seizures (NS). Current
treatments are both ineffective and potentially harmful. The central hypothesis of this proposal is that neonatal
seizures independently worsen brain injury after neonatal HI. Whether neonatal seizures are a critical second
hit after HI or just a biomarker of injury severity has been a long-debated question and we now have the
technologies available to address it at the temporal and cellular resolution necessary to answer it. Specifically,
in vivo real-time monitoring of seizures and neuronal death overcomes many of the limitations of past studies
to enable a more rigorous understanding of these dynamic processes. The immediate goals of this proposal
are to validate two-photon imaging methods for in vivo real-time seizure and cell death monitoring in a neonatal
pup and to define the relationship between neuronal seizure burden and the probability of cell death in a
neonatal HI model. Transgenic mouse lines expressing neuronal fluorescent proteins and calcium indicators
will undergo neonatal HI and be followed with chronic time-lapse two-photon imaging. The experiments
proposed will generate high-resolution correlational data between seizure burden and the probability of
neuronal death. The long-term goal is to obtain definitive data indicating whether NS are independently harmful
or not after HI, which is essential to determine how aggressively to treat patients and how to prioritize research
efforts to develop improved NS treatment strategies. The techniques and data acquired in this proposal will be
applied to future NIH-funded studies by the applicant to examine these processes and test treatments in this
clinically relevant pathophysiologic condition.
This proposal combines innovative and rigorous methodologies with directly translational implications,
excellent mentorship in science and career development in the laboratory as well as through the applicant's
scientific advisory committee, and extensive institutional resources at Massachusetts General Hospital and
Harvard Medical School. Completing the proposed aims in conjunction with the applicant's career development
plan will lead to the independence of the applicant as a clinician-scientist by the end of the award period. The
proposal closely reflects the applicant's research and clinical interests and provides key training to accomplish
the applicant's long-term career goal to become an expert in the clinical care of neonates and infants with
epilepsy while conducting laboratory-based research into mechanisms of and therapeutic strategies for brain
injury, seizures, and epileptogenesis in the developing brain.
项目总结/摘要
缺氧缺血性脑损伤(HI)每1,000例足月分娩中有2-6例并发症,
死亡率和不良的神经学结果。HI也是新生儿癫痫发作(NS)的主要原因。电流
治疗既无效又可能有害。这一建议的核心假设是,
癫痫发作独立地加重新生儿HI后的脑损伤。新生儿癫痫是否是一个关键的第二
HI后的撞击或只是损伤严重程度的生物标志物一直是一个长期争论的问题,我们现在有了
现有的技术可以在回答它所需的时间和细胞分辨率上解决它。具体来说,
在体内实时监测癫痫发作和神经元死亡克服了过去研究的许多局限性
来更好地理解这些动态过程。该提案的近期目标是
是为了验证双光子成像方法在体内实时癫痫发作和细胞死亡监测新生儿
幼崽并定义神经元癫痫发作负荷与细胞死亡概率之间的关系
新生儿HI模型。表达神经元荧光蛋白和钙指示剂的转基因小鼠系
将进行新生儿HI,随后进行慢性延时双光子成像。实验
建议将产生高分辨率的癫痫发作负担和概率之间的相关数据,
神经元死亡长期目标是获得明确的数据表明NS是否是独立有害的
这对于确定如何积极治疗患者以及如何优先考虑研究至关重要
努力开发改进的NS治疗策略。本建议书中获得的技术和数据将
申请人将其应用于未来NIH资助的研究,以检查这些过程并测试治疗方法。
临床相关病理生理状况。
该提案将创新和严格的方法与直接的翻译影响相结合,
在实验室的科学和职业发展,以及通过申请人的优秀导师
科学咨询委员会,以及马萨诸塞州总医院的广泛机构资源,
哈佛医学院。结合申请人的职业发展完成拟议目标
该计划将导致申请人在奖励期结束时作为临床科学家独立。的
提案密切反映了申请人的研究和临床兴趣,并提供了关键的培训,以完成
申请人的长期职业目标是成为新生儿和婴儿临床护理专家,
癫痫,同时进行基于实验室的研究机制和治疗策略,
损伤、癫痫发作和癫痫发生。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Melanie A McNally其他文献
Melanie A McNally的其他文献
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{{ truncateString('Melanie A McNally', 18)}}的其他基金
Neuronal Seizure Burden versus Cell Death after Neonatal Brain Injury
新生儿脑损伤后神经元癫痫负担与细胞死亡
- 批准号:
10373067 - 财政年份:2021
- 资助金额:
$ 20.09万 - 项目类别:
Neuronal Seizure Burden versus Cell Death after Neonatal Brain Injury
新生儿脑损伤后神经元癫痫发作负担与细胞死亡
- 批准号:
10191589 - 财政年份:2021
- 资助金额:
$ 20.09万 - 项目类别:
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