Regulation of seizure timing by circadian rhythms and sleep

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.