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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要候选人和职业发展计划：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。 K08 提案建立在我在儿科遗传疾病方面的经验以及我使用细胞和小鼠模型系统，以培养飞行模型系统方面的专业知识为重点。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) 昼夜节律/睡眠障碍遗传学方面的进一步临床专业知识；3) 发展导师技能，重点是促进科学和医学的多样性。该提案将使我能够启动自己的独立 R01 资助的研究项目，研究相互作用使用跨物种方法研究遗传性癫痫、昼夜节律和睡眠之间的关系。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) 主办了大型神经科学项目。宾夕法尼亚大学拥有最先进的资源和设施，是时间生物学和睡眠学的所在地。研究所 (CSI)，世界上最大的致力于昼夜节律和睡眠研究的中心之一。 CSI 主任是我的主要导师 Amita Sehgal 博士，他是 HHMI 研究员和国际专家她使用苍蝇模型系统研究昼夜节律和睡眠，并成功指导了多名医生。我的合作导师埃里克·马什 (Eric Marsh) 医学博士、哲学博士是负责开展 R01 资助的独立研究项目的科学家。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。研究提案：本研究提案的目标是了解是什么调节了癫痫发作的时间。新出现的数据表明，癫痫发作并不是随机发生的；癫痫发作实际上每天都会发生。因此，控制癫痫患者癫痫发作风险的这些周期的目标尚不清楚。该提案旨在利用研究生物节律的黄金标准——果蝇，来识别新的生物节律。调节癫痫节律的机制对细胞和回路机制的基本了解。控制癫痫发作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可能是调节日常癫痫发作的最佳循环内源性生物线索。时间是（1）昼夜节律和（2）睡眠/觉醒状态，因为昼夜节律的细胞回路不同。节律和睡眠/觉醒状态在果蝇中得到了很好的表征，我将应用这些知识来识别我将测试大脑中的中央时钟神经元是否是一天中癫痫发作时间波动的机制。昼夜节律的主要调节器，控制癫痫风险（目标 1），和/或参与睡眠/觉醒的回路通过使用飞行模型系统的力量，我将提供新颖的行为控制癫痫风险（目标2）。关于调节每日癫痫发作时间的机制的见解。