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

项目总结 这份辅导式职业发展奖提案描述了一个综合培训计划，为我做好准备 领导一个由R01资助的专注于癫痫研究的独立生物医学研究实验室。 应聘者：我是麻省理工大学神经内科的讲师和研究员 宾夕法尼亚大学(宾夕法尼亚)。我是一名获得董事会认证的神经科医生，同时也是一名有专业知识的巡回神经学家。 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 方法脑片和活体实验。我的长期目标是使用临床前癫痫小鼠模型来激励 开发以机械为导向的治疗方法，以改变患者护理。 环境：我将得到戈德伯格博士(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。 戈德堡博士是费城儿童医院的神经学和神经科学助理教授 (盖章)。他是系里一颗冉冉升起的新星，为我提供了无价的实践培训。 从一名成功的初级教员和内科科学家的角度出发，提供板凳和指导。 詹森博士是神经内科的主任。她是一位杰出的癫痫内科科学家， 对导师的热情和良好的履历。我和我的导师们建立了一种导师关系 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 具有广泛的资源和科学互动的机会，包括广泛的可用 神经科学、神经学和癫痫方面的课程作业和多个正在进行的研讨会系列。此应用程序是 得到了宾夕法尼亚大学神经科的热情支持。 研究：我在戈德堡博士实验室的初步实验发现了一种深刻的过度兴奋 在遗传性癫痫小鼠模型(Scn1a+/-)的皮质-海马区回路中，提示存在电路水平的 与获得性颞叶癫痫小鼠模型的趋同性。拟议的研究将确定 这一发现背后的微电路，并将检验这一电路对产生 颞叶的癫痫发作。这些结果将提供对这一重要机制的新见解 遗传性癫痫，以及建立更广泛的电路水平的发病机制在颞叶- 癫痫发作。这个有指导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。

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.