Cortico-hippocampal circuit dysfunction in an Scn1a mouse model of epilepsy

Scn1a 小鼠癫痫模型中的皮质-海马回路功能障碍

• 批准号: 10609318
• 负责人: Joanna H Mattis
• 金额: $ 19.49万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609318
• 关键词: Action Potentials; Affect; Award; Biomedical Research; Brain; Calcium; Cells; Choking; Chronic Disease; Clinic; Clinical; Communities; Data; Department chair; Development; Development Plans; Doctor of Philosophy; Electrophysiology (science); Ensure; Environment; Epilepsy; Etiology; Exhibits; Experimental Models; Faculty; Fellowship; Functional disorder; Funding; Future; Generations; Genes; Genetic; Genetic Models; Glean; Goals; Head; Hippocampus (Brain); Image; Impairment; Injury; Institution; Interneurons; Intractable Epilepsy; Investigational Therapies; K-Series Research Career Programs; Knowledge; Laboratories; Laboratory Research; Lead; Link; Measures; Mediating; Mentors; Mentorship; Methods; Monitor; Motivation; Mus; Mutation; National Institute of Neurological Disorders and Stroke; Neurologist; Neurology; Neurons; Neurosciences; Neurosciences Research; Outcome; Parvalbumins; Pathogenesis; Pathology; Patient Care; Patients; Pediatric Hospitals; Pennsylvania; Perforant Pathway; Persons; Philadelphia; Physicians; Physiology; Positioning Attribute; Refractory; Research; Resources; Rodent Model; Role; Scientist; Seizures; Series; Signal Transduction; Slice; Sodium Channel; Status Epilepticus; Synapses; Techniques; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Training; Training Programs; Translating; United States; United States National Institutes of Health; University Hospitals; Whole-Cell Recordings; base; career; career development; dentate gyrus; design; entorhinal cortex; experimental study; gamma-Aminobutyric Acid; granule cell; imaging modality; in vivo; insight; instructor; member; mouse model; neuronal circuitry; new therapeutic target; novel; optogenetics; patch clamp; pre-clinical; professor; recruit; response; skills; targeted treatment; therapy development; treatment optimization; two-photon

PROJECT SUMMARY This mentored career development award proposal describes an integrated training program to prepare me to lead an independent R01-funded biomedical research laboratory focused on the study of epilepsy. Candidate: I am an Instructor and Research Fellow in the Department of Neurology at the Hospital of the University of Pennsylvania (Penn). I am a board-certified neurologist and a circuit neuroscientist with expertise in the technique of optogenetics, gained through my PhD in the laboratory of Dr. Karl Deisseroth. This proposal is designed to fill my gaps in expertise in experimental epileptology and in state-of-the-art large-scale imaging methods in brain slice and in vivo. My long-term goal is to use pre-clinical mouse models of epilepsy to motivate development of mechanistically oriented therapies to transform patient care. Environment: I will have dual-mentorship from Dr. Goldberg (primary mentor) and Dr. Jensen (co-mentor and senior career mentor), who have together successfully co-mentored my NIH NINDS R25 research fellowship. Dr. Goldberg is an Assistant Professor of Neurology and Neuroscience at the Children's Hospital of Philadelphia (CHOP). He is a rising star in the department who has provided me with invaluable hands-on training at the bench as well as mentorship from the perspective of a successful junior faculty member and physician-scientist. Dr. Jensen is Chair of the Department of Neurology. She is an outstanding physician-scientist in epilepsy with a passion for and well-established track record of mentorship. My mentors and I have constructed a mentorship team and career development plan to guide the execution of the proposed studies and my transition to independence. Training will occur at CHOP and at Penn, an academically enriching neuroscience community with extensive resources and opportunities for scientific interaction, including a wide range of available coursework and multiple ongoing seminar series in neuroscience, neurology, and epilepsy. This application is supported enthusiastically by the Department of Neurology at Penn. Research: My preliminary experiments in Dr. Goldberg’s laboratory have identified a profound hyperexcitability in the cortico-hippocampal circuit within a mouse model of genetic epilepsy (Scn1a+/-), suggesting a circuit-level convergence with mouse models of acquired temporal lobe epilepsy. The proposed research will identify the microcircuitry underlying this finding, and will test the hypothesis that this circuit is critical for the generation of seizures in the temporal lobe. These outcomes will provide novel insights into mechanisms of this important genetic epilepsy, as well as establishing more broadly a circuit-level pathogenesis underlying temporal lobe- onset seizures. This mentored career development award will position me to translate the insights gleaned from basic neuroscience research to inform and motivate future attempts at the targeted treatment of epilepsy.

项目摘要 这份指导式职业发展奖励计划描述了一个综合培训计划， 领导一个独立的R 01资助的生物医学研究实验室，专注于癫痫的研究。 候选人：我是一名讲师和研究员，在神经科在医院的 宾夕法尼亚大学（Penn）我是一名经过委员会认证的神经学家和电路神经学家， 在光遗传学技术方面，我在卡尔·戴瑟罗斯博士的实验室获得了博士学位。这项建议 旨在填补我在实验癫痫学和最先进的大规模成像方面的专业知识空白 脑切片和活体方法。我的长期目标是使用临床前癫痫小鼠模型来激发 发展以机械为导向的疗法，以改变病人的护理。 环境：我将得到Goldberg博士（主要导师）和詹森博士（共同导师和 高级职业导师），他们一起成功地共同指导了我的NIH NINDS R25研究奖学金。 博士戈德堡是费城儿童医院神经病学和神经科学的助理教授 （CHOP）。他是系里一颗冉冉升起的星星，他为我提供了宝贵的实践培训， 从一个成功的初级教师和医生科学家的角度来看，板凳以及导师。 博士詹森是神经病学系主任。她是一个杰出的物理学家，科学家在癫痫与 对指导的热情和良好的跟踪记录。我和我的导师们建立了一个 团队和职业发展计划，以指导执行拟议的研究和我的过渡到 独立培训将在CHOP和宾夕法尼亚大学进行，这是一个学术上丰富的神经科学社区 拥有广泛的资源和机会进行科学互动，包括广泛的可用 课程和多个正在进行的神经科学，神经病学和癫痫系列研讨会。本申请是 得到了宾夕法尼亚大学神经病学系的热情支持。 研究：我在戈德堡博士实验室的初步实验已经确定了一种深刻的过度兴奋。 在遗传性癫痫（Scn 1a +/-）小鼠模型中的皮质-海马回路中， 与获得性颞叶癫痫的小鼠模型的会聚。拟议的研究将确定 微电路的基础上这一发现，并将测试的假设，这一电路是至关重要的产生 颞叶癫痫这些结果将为这一重要的机制提供新的见解。 遗传性癫痫，以及建立更广泛的电路水平的发病机制，颞叶- 癫痫发作这个指导性的职业发展奖将使我能够翻译从 基础神经科学研究，为癫痫的靶向治疗提供信息和激励未来的尝试。