Mechanisms of PCDH19-clustering epilepsy
PCDH19 丛集性癫痫的机制
基本信息
- 批准号:10588779
- 负责人:
- 金额:$ 23.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-01-15 至 2027-11-30
- 项目状态:未结题
- 来源:
- 关键词:Abnormal CellAcuteAffectAllelesBrainCalciumCell Adhesion MoleculesCell CommunicationCell Culture TechniquesCell DeathCell ProliferationCell SeparationCell membraneCellsComplementDataDevelopmentDevelopment PlansDevelopmental Therapeutics ProgramDiseaseDoctor of MedicineDoctor of PhilosophyElectrophysiology (science)EmbryoEpilepsyExcitatory SynapseFemaleFutureGenesGeneticGoalsHippocampusHistologicImageImaging TechniquesImpaired cognitionImpairmentIn VitroIndividualInduced HyperthermiaInheritance PatternsInhibitory SynapseInterneuronsKnowledgeLabelLearningLifeLinkMeasuresMedialMentorsModelingMusNeuronsNeurosciences ResearchParvalbuminsPathogenicityPatientsPatternPediatric NeurologyPhysiciansPhysiologicalPopulationPrecision therapeuticsPredispositionProcessProgram DevelopmentProliferatingProsencephalonPyramidal CellsReporterReportingResearchResearch DesignResearch PersonnelRodentRoleScientistSeizuresSignal TransductionSliceSynapsesTestingTherapeuticTrainingTraining ActivityTranslational ResearchVariantViralViral VectorVisualizationWorkX Inactivationacquired epilepsycareercareer developmentcell motilitychildhood epilepsyclinical trainingclinical translationclinically relevantdensitydesignepileptic encephalopathiesexperiencefield studygirlsin vivoinfancyinhibitory neuroninsightmalemedical specialtiesmigrationmosaicmosaic variantmouse modelmutantneuron developmentneuropsychiatryoffspringpatch clamppostnatalprogenitorprotocadherin 19segregationskillstherapeutic target
项目摘要
PROJECT SUMMARY/ABSTRACT
This proposal describes a five-year career development program that will lead the PI to a career as an
independent physician-scientist, studying mechanisms and potential therapeutics of developmental and
epileptic encephalopathies.
Applicant: Dr. Ziobro holds M.D. and Ph.D. degrees and has completed specialty clinical training in both Child
Neurology and Pediatric Epilepsy. She has previous experience in neuroscience research using rodent,
neuronal cell culture, and organotypic hippocampal cell culture models of acquired epilepsy. This career
development plan includes a period of mentored research designed to develop the applicant’s knowledge in
advanced imaging techniques, viral vector design, brain slice electrophysiology, and interneuron development.
These skills will complement her current skill-set and propel her development as an independent researcher.
The concepts learned during this training period will be broadly applicable to multiple disease processes and
allow for significant clinical translation in a clinically relevant field of study.
Research Plan: PCDH19-clustering epilepsy (PCE) is one of the most common monogenic developmental
and epileptic encephalopathies (DEEs), characterized by cognitive impairment and intractable seizure clusters
starting in infancy. PCDH19 is and X-linked gene that encodes a transmembrane cell adhesion molecule,
critical for cell interactions during brain development. PCE affects females and rare mosaic males, while males
expressing only mutant PCDH19 do not develop epilepsy. A leading hypothesis to explain this phenomenon is
that it occurs due to cellular interference associated with random X-inactivation (or mosaic mutations) in which
cells expressing wild type and those expressing mutant PCDH19 fail to interact properly during brain
development, which is supported by a preliminary data showing a unique cell segregation pattern of Pcdh19+
and Pcdh19- neurons in the cortex and hippocampus of the PCE mouse model. Our central hypothesis is that
mosaic Pcdh19 expression alters interneuron development in the hippocampal CA1 region leading to aberrant
network formation, hyperexcitability and increased seizure susceptibility. This proposal will characterize
histologic (Aim 1) physiologic (Aim 2) and developmental (Aim 3) mechanisms of PCE. This study will provide
significant insight into the mechanisms of PCE and guide potential therapeutic strategies that may be
applicable to multiple genetic epilepsies.
项目概要/摘要
该提案描述了一个为期五年的职业发展计划,该计划将引导 PI 成为一名
独立医师科学家,研究发育和发育的机制和潜在疗法
癫痫性脑病。
申请人:Ziobro 博士拥有医学博士和博士学位。学位并完成了儿童和儿童的专业临床培训
神经病学和小儿癫痫。她之前有使用啮齿动物进行神经科学研究的经验,
神经元细胞培养和获得性癫痫的器官型海马细胞培养模型。这个职业
发展计划包括一段指导研究,旨在发展申请人的知识
先进的成像技术、病毒载体设计、脑切片电生理学和中间神经元发育。
这些技能将补充她当前的技能,并推动她作为独立研究员的发展。
在本次培训期间学到的概念将广泛适用于多种疾病过程和
允许在临床相关研究领域进行重要的临床转化。
研究计划:PCDH19丛集性癫痫(PCE)是最常见的单基因发育性癫痫之一
和癫痫性脑病(DEE),其特征是认知障碍和顽固性癫痫发作
从婴儿期开始。 PCDH19 是编码跨膜细胞粘附分子的 X 连锁基因,
对于大脑发育过程中的细胞相互作用至关重要。 PCE 影响女性和罕见的镶嵌男性,而男性
仅表达突变型 PCDH19 不会发展为癫痫。解释这种现象的一个主要假设是
它的发生是由于与随机 X 失活(或嵌合突变)相关的细胞干扰,其中
表达野生型的细胞和表达突变型 PCDH19 的细胞在大脑过程中无法正常相互作用
开发,得到了初步数据的支持,显示了 Pcdh19+ 独特的细胞分离模式
PCE 小鼠模型皮层和海马中的 Pcdh19- 神经元。我们的中心假设是
马赛克 Pcdh19 表达改变海马 CA1 区中间神经元发育,导致异常
网络形成、过度兴奋和癫痫易感性增加。该提案将描述
PCE 的组织学(目标 1)生理(目标 2)和发育(目标 3)机制。这项研究将提供
对 PCE 机制的重要见解并指导可能的潜在治疗策略
适用于多种遗传性癫痫。
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)
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Julie M Ziobro其他文献
Julie M Ziobro的其他文献
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