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Mystery Solved with Math: Cytoplasmic Traffic Jam Disrupts Sleep-Wake Cycles
KAIST mathematicians and their collaborators at Florida State University have identified the principle of how aging and diseases like dementia and obesity cause sleep disorders. A combination of mathematical modelling and experiments demonstrated that the cytoplasmic congestion caused by aging, dementia, and/or obesity disrupts the circadian rhythms in the human body and leads to irregular sleep-wake cycles. This finding suggests new treatment strategies for addressing unstable sleep-wake cycles. Human bodies adjust sleep schedules in accordance with the ‘circadian rhythms’, which are regulated by our time keeping system, the ‘circadian clock’. This clock tells our body when to rest by generating the 24-hour rhythms of a protein called PERIOD (PER) (See Figure 1). The amount of the PER protein increases for half of the day and then decreases for the remaining half. The principle is that the PER protein accumulating in the cytoplasm for several hours enters the cell nucleus all at once, hindering the transcription of PER genes and thereby reducing the amount of PER. However, it has remained a mystery how thousands of PER molecules can simultaneously enter into the nucleus in a complex cell environment where a variety of materials co-exist and can interfere with the motion of PER. This would be like finding a way for thousands of employees from all over New York City to enter an office building at the same time every day. A group of researchers led by Professor Jae Kyoung Kim from the KAIST Department of Mathematical Sciences solved the mystery by developing a spatiotemporal and probabilistic model that describes the motion of PER molecules in a cell environment. This study was conducted in collaboration with Professor Choogon Lee’s group from Florida State University, where the experiments were carried out, and the results were published in the Proceedings of the National Academy of Sciences (PNAS) last month. The joint research team’s spatial stochastic model (See Figure 2) described the motion of PER molecules in cells and demonstrated that the PER molecule should be sufficiently condensed around the cell nucleus to be phosphorylated simultaneously and enter the nucleus together (See Figure 3 Left). Thanks to this phosphorylation synchronization switch, thousands of PER molecules can enter the nucleus at the same time every day and maintain stable circadian rhythms. However, when aging and/or diseases including dementia and obesity cause the cytoplasm to become congested with increased cytoplasmic obstacles such as protein aggregates and fat vacuoles, it hinders the timely condensation of PER molecules around the cell nucleus (See Figure 3 Right). As a result, the phosphorylation synchronization switch does not work and PER proteins enter into the nucleus at irregular times, making the circadian rhythms and sleep-wake cycles unstable, the study revealed. Professor Kim said, “As a mathematician, I am excited to help enable the advancement of new treatment strategies that can improve the lives of so many patients who suffer from irregular sleep-wake cycles. Taking these findings as an opportunity, I hope to see more active interchanges of ideas and collaboration between mathematical and biological sciences.” This work was supported by the National Institutes of Health and the National Science Foundation in the US, and the International Human Frontiers Science Program Organization and the National Research Foundation of Korea. Publication: Beesley, S. and Kim, D. W, et al. (2020) Wake-sleep cycles are severely disrupted by diseases affecting cytoplasmic homeostasis. Proceedings of the National Academy of Sciences (PNAS), Vol. 117, No. 45, 28402-28411. Available online at https://doi.org/10.1073/pnas.2003524117 Profile: Jae Kyoung Kim, Ph.D. Associate Professor firstname.lastname@example.org http://mathsci.kaist.ac.kr/~jaekkim @umichkim on Twitter Department of Mathematical Sciences Korea Advanced Institute of Science and Technology (KAIST) Daejeon, Republic of Korea Profile: Choogon Lee, Ph.D. Associate Professor email@example.com https://med.fsu.edu/biosci/lee-lab Department of Biomedical Sciences Florida State University Florida, USA (END)
Mathematical Modeling Makes a Breakthrough for a New CRSD Medication
PhD Candidate Dae Wook Kim (Left) and Professor Jae Kyoung Kim (Right) - Systems approach reveals photosensitivity and PER2 level as determinants of clock-modulator efficacy - Mathematicians’ new modeling has identified major sources of interspecies and inter-individual variations in the clinical efficacy of a clock-modulating drug: photosensitivity and PER2 level. This enabled precision medicine for circadian disruption. A KAIST mathematics research team led by Professor Jae Kyoung Kim, in collaboration with Pfizer, applied a combination of mathematical modeling and simulation tools for circadian rhythms sleep disorders (CRSDs) to analyze the animal data generated by Pfizer. This study was reported in Molecular Systems Biology as the cover article on July 8. Pharmaceutical companies have conducted extensive studies on animals to determine the candidacy of this new medication. However, the results of animal testing do not always translate to the same effects in human trials. Furthermore, even between humans, efficacy differs across individuals depending on an individual’s genetic and environmental factors, which require different treatment strategies. To overcome these obstacles, KAIST mathematicians and their collaborators developed adaptive chronotherapeutics to identify precise dosing regimens that could restore normal circadian phase under different conditions. A circadian rhythm is a 24-hour cycle in the physiological processes of living creatures, including humans. A biological clock in the hypothalamic suprachiasmatic nucleus in the human brain sets the time for various human behaviors such as sleep. A disruption of the endogenous timekeeping system caused by changes in one’s life pattern leads to advanced or delayed sleep-wake cycle phase and a desynchronization between sleep-wake rhythms, resulting in CRSDs. To restore the normal timing of sleep, timing of the circadian clock could be adjusted pharmacologically. Pfizer identified PF-670462, which can adjust the timing of circadian clock by inhibiting the core clock kinase of the circadian clock (CK1d/e). However, the efficacy of PF-670462 significantly differs between nocturnal mice and diurnal monkeys, whose sleeping times are opposite. The research team discovered the source of such interspecies variations in drug response by performing thousands of virtual experiments using a mathematical model, which describes biochemical interactions among clock molecules and PF-670462. The result suggests that the effect of PF-670462 is reduced by light exposure in diurnal primates more than in nocturnal mice. This indicates that the strong counteracting effect of light must be considered in order to effectively regulate the circadian clock of diurnal humans using PF-670462. Furthermore, the team also found the source of inter-patients variations in drug efficacy using virtual patients whose circadian clocks were disrupted due to various mutations. The degree of perturbation in the endogenous level of the core clock molecule PER2 affects the efficacy. This explains why the clinical outcomes of clock-modulating drugs are highly variable and certain subtypes are unresponsive to treatment. Furthermore, this points out the limitations of current treatment strategies tailored to only the patient’s sleep and wake time but not to the molecular cause of sleep disorders. PhD candidate Dae Wook Kim, who is the first author, said that this motivates the team to develop an adaptive chronotherapy, which identifies a personalized optimal dosing time of day by tracking the sleep-wake up time of patients via a wearable device and allows for a precision medicine approach for CRSDs. Professor Jae Kyoung Kim said, "As a mathematician, I am excited to help enable the advancement of a new drug candidate, which can improve the lives of so many patients. I hope this result promotes more collaborations in this translational research.” This research was supported by a Pfizer grant to KAIST (G01160179), the Human Frontiers Science Program Organization (RGY0063/2017), and a National Research Foundation (NRF) of Korea Grant (NRF-2016 RICIB 3008468 and NRF-2017-Fostering Core Leaders of the Future Basic Science Program/ Global Ph.D. Fellowship Program). Figure 1. Interspecies and Inter-patients Variations in PF-670462 Efficacy Figure 2. Journal Cover Page Publication: Dae Wook Kim, Cheng Chang, Xian Chen, Angela C Doran, Francois Gaudreault, Travis Wager, George J DeMarco, and Jae Kyoung Kim. 2019. Systems approach reveals photosensitivity and PER2 level as determinants of clock-modulator efficacy. Molecular Systems Biology. EMBO Press, Heidelberg, Germany, Vol. 15, Issue No. 7, Article, 16 pages. https://doi.org/10.15252/msb.20198838 Profile: Prof. Jae Kyoung Kim, PhD firstname.lastname@example.org http://mathsci.kaist.ac.kr/~jaekkim Associate Professor Department of Mathematical Sciences Korea Advanced Institute of Science and Technology (KAIST) http://kaist.ac.kr Daejeon 34141, Korea Profile: Dae Wook Kim, PhD Candidate email@example.com http://mathsci.kaist.ac.kr/~jaekkim PhD Candidate Department of Mathematical Sciences Korea Advanced Institute of Science and Technology (KAIST) http://kaist.ac.kr Daejeon 34141, Korea Profile: Dr. Cheng Chang, PhD firstname.lastname@example.org Associate Director of Clinical Pharmacology Clinical Pharmacology, Global Product Development Pfizer https://www.pfizer.com/ Groton 06340, USA (END)
Blue-enriched White Light to Wake You Up in the Morning
(from left: Professor Hyun Jung Chung, Professor Hyeon-Jeong Suk, Taesu Kim and Professor Kyungah Choi) Here is a good news for those of who have difficulty with morning alertness. A KAIST research team proposed that a blue-enriched LED light can effectively help people overcome morning drowsiness. This study will provide the basis for major changes in future lighting strategies and thereby help create better indoor environments. Considerable research has been devoted to unmasking circadian rhythms. The 2017 Nobel Prize in Physiology or Medicine went to Jeffrey C. Hall, Michael Rosbash, and Michael W. Young for unveiling the molecular mechanisms that control circadian rhythms. In particular, the relationship between light and its physiological effects has been investigated since the discovery of a novel, third type of photoreceptor in the human retina in the early 2000s. Rods and cones regulate visual effects, while the third type, photosensitive retinal ganglion cells, regulate a large variety of biological and behavioral processes including melatonin and cortisol secretion, alertness, and functional magnetic resonance imaging (fMRI). Initial studies on light sources have shown that blue monochromatic, fully saturated lights are effective for stimulating physiological responses, but the relative effectiveness of commercially available white light sources is less well understood. Moreover, the research was more focused on the negative effects of blue light; for instance, when people are exposed to blue light at night, they have trouble achieving deep sleep because the light restrains melatonin secretion. However, Professor Hyeon-Jeong Suk and Professor Kyungah Choi from the Department of Industrial Design and their team argue that the effects of blue-enriched morning light on physiological responses are time dependent, and that it has positive effects on melatonin levels and the subjective perception of alertness, mood, and visual comfort compared with warm white light. The team conducted an experiment with 15 university students. They investigated whether an hour of morning light exposure with different chromaticity would affect their physiological and subjective responses differently. The decline of melatonin levels was significantly greater after the exposure to blue-enriched white light in comparison with warm white light. Professor Suk said, “Light takes a huge part of our lives since we spend most of our time indoors. Light is one of the most powerful tools to affect changes in how we perceive and experience the environment around us.” Professor Choi added, “When we investigate all of the psychological and physiological effects of light, we see there is much more to light than just efficient quantities. I believe that human-centric lighting strategies could be applied to a variety of environments, including residential areas, learning environments, and working spaces to improve our everyday lives.” This research was collaborated with Professor Hyun Jung Chung from the Graduate School of Nanoscience and Technology and was published in Scientific Reports (10.1038/s41598-018-36791-5) on January 23, 2019. Figure 1. Changes in melatonin secretion during day and night time
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