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.

项目总结/摘要 候选人和职业发展计划：我是一名临床神经遗传学家，具有分子生物学背景。 研究神经遗传疾病、昼夜节律和睡眠之间相互作用的神经科学。这 K 08的建议建立在我在儿科遗传疾病方面的经验，以及我的博士学位使用细胞和 小鼠模型系统，建立专门的苍蝇模型系统。我的职业发展计划专注于 在三个需要培训的领域：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）进一步的昼夜节律/睡眠障碍遗传学临床专业知识;以及3） 发展指导技能，重点是促进科学和医学的多样性。K08 我的建议将使我能够启动我自己的独立R 01资助的研究计划，研究相互作用 遗传性癫痫、昼夜节律和睡眠之间的关系。 环境和导师制：我的培训计划利用了北京市儿童医院提供的机会。 费城（CHOP）和宾夕法尼亚大学（UPenn）。CHOP和宾夕法尼亚大学主办了一个大型神经科学 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 研究所（CSI）是世界上最大的致力于昼夜节律和睡眠研究的中心之一。的 CSI主任是我的主要导师Amita Sehgal博士，HHMI调查员和国际专家， 昼夜节律和睡眠使用苍蝇模型系统。她成功地指导了多名医生 科学家们运行独立的R 01资助的研究项目。我的共同导师，埃里克马什，医学博士，博士，是一个 成功的神经遗传学家和癫痫病学家，他将监督我的持续临床发展。 研究提案：本研究提案的目标是了解是什么调节癫痫发作的时间。 新出现的数据表明，癫痫发作的发生不是随机的;癫痫发作实际上每天都发生。 自行车.是什么控制癫痫患者癫痫发作风险的这些周期尚不清楚。因此， 这个建议是使用研究生物节律的金标准，果蝇， 调节癫痫发作节律的机制。对细胞和电路机制有基本的了解 控制癫痫发作时间可能揭示治疗干预的新途径，并提高我们的能力， 预测癫痫发作最受赞赏的周期性内源性生物线索，可能是调节日常癫痫发作 定时是（1）昼夜节律和（2）睡眠/觉醒状态。因为昼夜节律的独特细胞回路 节奏和睡眠/觉醒状态的特点是苍蝇，我将应用这些知识来确定 癫痫发作的时间波动机制。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/或是否涉及睡眠/觉醒回路 行为控制癫痫发作风险（目标2）。通过使用飞模系统的力量，我将提供新颖的 关于什么调节癫痫发作的每日时间的机械见解。