Mechanisms of PCDH19-clustering epilepsy

PCDH19 丛集性癫痫的机制

• 批准号: 10588779
• 负责人: Julie M Ziobro
• 金额: $ 23.06万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10588779
• 关键词: Abnormal Cell; Acute; Affect; Alleles; Brain; Calcium; Cell Adhesion Molecules; Cell Communication; Cell Culture Techniques; Cell Death; Cell Proliferation; Cell Separation; Cell membrane; Cells; Complement; Data; Development; Development Plans; Developmental Therapeutics Program; Disease; Doctor of Medicine; Doctor of Philosophy; Electrophysiology (science); Embryo; Epilepsy; Excitatory Synapse; Female; Future; Genes; Genetic; Goals; Hippocampus; Histologic; Image; Imaging Techniques; Impaired cognition; Impairment; In Vitro; Individual; Induced Hyperthermia; Inheritance Patterns; Inhibitory Synapse; Interneurons; Knowledge; Label; Learning; Life; Link; Measures; Medial; Mentors; Modeling; Mus; Neurons; Neurosciences Research; Parvalbumins; Pathogenicity; Patients; Pattern; Pediatric Neurology; Physicians; Physiological; Population; Precision therapeutics; Predisposition; Process; Program Development; Proliferating; Prosencephalon; Pyramidal Cells; Reporter; Reporting; Research; Research Design; Research Personnel; Rodent; Role; Scientist; Seizures; Signal Transduction; Slice; Synapses; Testing; Therapeutic; Training; Training Activity; Translational Research; Variant; Viral; Viral Vector; Visualization; Work; X Inactivation; acquired epilepsy; career; career development; cell motility; childhood epilepsy; clinical training; clinical translation; clinically relevant; density; design; epileptic encephalopathies; experience; field study; girls; in vivo; infancy; inhibitory neuron; insight; male; medical specialties; migration; mosaic; mosaic variant; mouse model; mutant; neuron development; neuropsychiatry; offspring; patch clamp; postnatal; progenitor; protocadherin 19; segregation; skills; therapeutic target

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 Pc​​dh19 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。