Regulation of seizure timing by circadian rhythms and sleep

通过昼夜节律和睡眠调节癫痫发作时间

• 批准号: 10643189
• 负责人: Vishnu Anand Cuddapah
• 金额: $ 21.53万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643189
• 关键词: Acute; Area; Automobile Driving; Behavior; Behavior Control; Biological; Biological Models; Biological Rhythm; Brain; CRISPR/Cas technology; Cell model; Childhood; Chronobiology; Circadian Rhythms; Clinical; Communities; Cues; Data; Dedications; Development; Disease; Doctor of Philosophy; Drosophila genus; Drowsiness; Electroencephalography; Environment; Epilepsy; Exhibits; Exposure to; Foundations; Funding; Future; Genetic; Genetic Diseases; Genetic Screening; Goals; Home; Hour; Individual; International; Knock-out; Knowledge; Mammals; Measures; Mediating; Mediator; Medicine; Mentors; Mentorship; Modeling; Modernization; Molecular; Molecular Biology Techniques; Motor; Neuromodulator; Neurons; Neurosciences; Neurotransmitters; Pathway interactions; Pattern; Pediatric Hospitals; Pennsylvania; Periodicity; Persons; Philadelphia; Physicians; Picrotoxin; Predisposition; Process; Regulation; Research; Research Personnel; Research Proposals; Resources; Risk; Running; Science; Scientist; Seizures; Severities; Sleep; Sleep Deprivation; Sleep Disorders; Stereotyping; Testing; Therapeutic Intervention; Time; Training; Universities; Variant; Visualization; Work; brain dysfunction; career development; cell type; circadian; circadian pacemaker; circadian regulation; clinical development; experience; experimental study; fly; improved; insight; interest; molecular clock; mouse model; mutant; neurogenetics; new therapeutic target; novel; pharmacologic; programs; receptor; skills

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.

项目摘要/摘要 候选人和职业发展计划：我是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疾病方面的经验以及使用蜂窝和博士学位的经验 鼠标模型系统，以在飞行模型系统中建立专业知识。我的职业发展计划集中在 在三个需要的培训领域：1）使用飞行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/睡眠障碍遗传学方面的进一步临床专业知识； 3） 发展质量技能，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自己的独立R01资助的研究计划，以研究互动 在遗传性癫痫，昼夜节律和使用跨物种方法的睡眠之间。 环境与指导：我的培训计划利用儿童医院可用的机会 费城（CHOP）和宾夕法尼亚大学（Upenn）。切碎和Upenn主持一个大型神经科学 具有最先进的资源和设施的社区。 Upenn是时间生物学和睡眠的家园 研究所（CSI）是全球最大的中心之一，致力于昼夜节律和睡眠研究。 CSI主任是我的主要心理，Amita Sehgal博士，HHMI调查员兼国际专家 使用飞行模型系统的昼夜节律和睡眠。她已经成功修补了多个医生 运行独立R01资助的研究计划的科学家。我的联合学者，医学博士埃里克·马什（Eric Marsh）是一个 成功的神经遗传学家和癫痫学家将监督我持续的临床发展。 研究建议：该研究建议的目的是了解是什么调节癫痫发作的时间。 新兴数据表明，癫痫发作的发生不是随机的。癫痫发作实际上每天发生 周期。癫痫患者中控制这些周期在癫痫发作风险中的原因是未知的。因此，目标的目标 该建议是使用黄金标准来研究生物节奏，即果蝇，以识别新型 调节癫痫发作节奏的机制。对细胞和电路机制的基本理解 控制癫痫发作的时机可能揭示了热干预的新途径，并提高了我们的能力 预测癫痫发作。最好的循环内源性生物学提示，可能正在调节每日癫痫发作 时间是（1）昼夜节律和（2）睡眠/唤醒状态。因为昼夜节律的独特的蜂窝电路 节奏和睡眠/唤醒状态在苍蝇中表现得很好，我将应用此知识来确定 癫痫发作的日期波动的基础的机制。我将测试中央时钟神经元是否在大脑中 昼夜节律的主调节器，控制癫痫发作风险（AIM 1）和/或如果参与睡眠/唤醒的电路 行为控制癫痫发作风险（AIM 2）。通过使用飞行模型系统的力量，我将提供新颖 关于调节日常癫痫发作时间的机械洞察力。