Regulation of seizure timing by circadian rhythms and sleep

项目摘要/摘要 求职者和职业发展规划：我是一名具有分子背景的临床神经遗传学家 神经科学对神经遗传疾病、昼夜节律和睡眠之间的相互作用感兴趣。这 K08提案建立在我在儿科遗传病方面的经验，以及我的博士学位使用细胞和 鼠标模型系统，专门构建苍蝇模型系统。我的职业发展计划是专注的 关于三个需要的培训领域：1)使用苍蝇模型系统和现代分子生物学技术 建立研究独立性；2)在昼夜节律/睡眠障碍的遗传学方面有进一步的临床专业知识；3) 发展指导技能，重点是促进科学和医学的多样性。这个K08 提案将使我能够启动我自己的独立R01资助的研究项目，研究相互作用 遗传性癫痫、昼夜节律和使用跨物种方法的睡眠之间的关系。 环境和指导：我的培训计划利用了儿童医院提供的机会 费城(CHOP)和宾夕法尼亚大学(UPenn)。Chop和UPenn主办了一场大型神经科学 拥有最先进的资源和设施的社区。宾夕法尼亚大学是时间生物学和睡眠的发源地 世界上最大的昼夜节律和睡眠研究中心之一。这个 CSI主任是我的主要导师，阿米塔·塞格尔博士，HHMI调查员和国际专家 使用苍蝇模型系统的昼夜节律和睡眠。她成功地指导了多名医生 运行R01资助的独立研究项目的科学家。我的合作导师埃里克·马什，医学博士，是一个 成功的神经遗传学家和癫痫专家，他将监督我的临床发展。 研究建议：本研究建议的目标是了解是什么控制了癫痫发作的时间。 新出现的数据表明，癫痫发作不是随机发生的；癫痫发作实际上每天都会发生 循环。在癫痫患者中，是什么控制了这些周期的发作风险尚不清楚。因此，目标是 这项提议是用研究生物节律的黄金标准--果蝇--来识别小说 调节癫痫发作节律性的机制。对细胞和电路机制有基本的了解 控制癫痫发作的时间可能会揭示治疗干预的新途径，并提高我们的能力 预测癫痫发作。最受欢迎的可能调节日常癫痫发作的循环内源性生物线索 计时是(1)昼夜节律和(2)睡眠/清醒状态。因为昼夜节律的独特细胞回路 苍蝇的节律和睡眠/清醒状态是很好的特征，我将应用这一知识来识别 癫痫发作中时间波动的基础机制。我将测试大脑中的中央时钟神经元， 昼夜节律的主要调节器，控制癫痫发作风险(目标1)，和/或是否有电路参与睡眠/觉醒 行为控制癫痫风险(目标2)。通过使用苍蝇模型系统的力量，我将提供新的 关于什么控制癫痫发作的每日时间的机械性洞察力。

PROJECT SUMMARY/ABSTRACT Candidate and Plan for Career Development: I am a clinical neurogeneticist with a background in molecular neuroscience interested in the interactions between neurogenetic disease, circadian rhythms, and sleep. This K08 proposal builds on my experience in pediatric genetic diseases, as well as my PhD using cellular and mouse model systems, to build expertise in the fly model system. My Plan for Career Development is focused on three needed training areas: 1) use of the fly model system and modern molecular biology techniques to establish research independence; 2) further clinical expertise in genetics of circadian/sleep disorders; and 3) development mentorship skills with an emphasis on promoting diversity in science and medicine. This K08 proposal will enable me to launch my own independent R01-funded research program studying the interaction between genetic epilepsies, circadian rhythms, and sleep using cross-species approaches. Environment and Mentorship: My training plan leverages the opportunities available at Children’s Hospital of Philadelphia (CHOP) and University of Pennsylvania (UPenn). CHOP and UPenn host a large neuroscience community with state-of-the-art resources and facilities. UPenn is home to the Chronobiology and Sleep Institute (CSI), one of the largest centers in the world dedicated to circadian rhythm and sleep research. The Director of the CSI is my primary mentor, Amita Sehgal, PhD, an HHMI Investigator and international expert in circadian rhythms and sleep using the fly model system. She has successfully mentored multiple physician scientists who run independent R01-funded research programs. My co-mentor, Eric Marsh, MD, PhD, is a successful neurogeneticist and epileptologist who will oversee my continued clinical development. Research Proposal: The goal of this research proposal is to understand what regulates the timing of seizures. Emerging data are demonstrating that seizure occurrence is not random; seizures actually occur in daily cycles. What controls these cycles in seizure risk in people with epilepsy is unknown. Therefore, the goal of this proposal is to use the gold standard for studying biological rhythms, the fruit fly, to identify novel mechanisms that regulate seizure rhythmicity. A basic understanding of the cellular and circuit mechanisms that control seizure timing may reveal novel pathways for therapeutic intervention and improve our ability to predict seizures. The best appreciated cyclic endogenous biological cues that may be regulating daily seizure timing are (1) circadian rhythms and (2) the sleep/wake state. Because the distinct cellular circuitry of circadian rhythms and sleep/wake state are well characterized in flies, I will apply this knowledge to identify the mechanisms that underlie time-of-day fluctuations in seizures. I will test if central clock neurons in the brain, the master regulator of circadian rhythms, controls seizure risk (Aim 1), and/or if circuits involved in sleep/wake behavior control seizure risk (Aim 2). By using the power of the fly model system, I will provide novel mechanistic insight as to what regulates the daily timing of seizures.