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Homeodynamics in Clocks, Sleep and Metabolism Homeodynamics in Clocks, Sleep and Metabolism TOKYO TRANSLATIONAL THERAPEUTICS MEETING Wednesday, September 24, 2014 at Ito Hall, Ito International Research Center, The University of Tokyo Organizing Committee Hiroki R. Ueda Joseph T. Bass Masashi Yanagisawa The University of Tokyo / RIKEN QBiC Northwestern University WPI-IIIS, University of Tsukuba Main Speakers Joseph T. Bass Hitoshi Okamura Joseph S. Takahashi Northwestern University Kyoto University UT Southwestern Medical Center Yang Dan John Renger Hiroki R. Ueda University of California, Berkeley Merck Research Laboratories University of Tokyo / RIKEN QBiC Takashi Kadowaki Hitoshi Shimano Masashi Yanagisawa University of Tokyo University of Tsukuba WPI-IIIS, University of Tsukuba Emmanuel Mignot Stanford University Discussants Ravi Allada Kazuhiko Kume Amita Sehgal Northwestern University Nagoya City University University of Pennsylvania Michael Hastings Michael Lazarus Susumu Seino University of Cambridge WPI-IIIS, University of Tsukuba Kobe University Samer Hattar Akhilesh Reddy Akihiro Yamanaka Johns Hopkins University University of Cambridge Nagoya University Yu Hayashi Sue-Goo Rhee Takashi Yoshimura WPI-IIIS, University of Tsukuba Yonsei University Nagoya University Takao Kondo Michael Rosbash Nagoya University Brandeis University Homeodynamics in Clocks, Sleep and Metabolism Program Wednesday, September 24, 2014 Opening Remarks Opening Address 1 Hiroki R. Ueda The University of Tokyo / RIKEN QBiC Opening Address 2 Nobutaka Hirokawa Fujihara Foundation of Science 9:20 - 9:40 Opening Address 3 Takashi Kadowaki The University of Tokyo WPI Program Director, Japan Society for the Opening Address 4 Toshio Kuroki Promotion of Science (JSPS) Session 1 - Sleep Chair: Michael Lazarus 9:40 - 9:45 Introductory Remarks Michael Lazarus WPI-IIIS, University of Tsukuba Forward genetic analysis of sleep in 9:45 - 10:15 Masashi Yanagisawa WPI-IIIS, University of Tsukuba ENU-mutagenized mice Neural circuits controlling sleep and 10:15 - 10:45 Yang Dan University of California, Berkeley wakefulness Orexin/hypocretin receptor antagonist 10:45 - 11:15 preclinical profile on sleep and John Renger Merck Research Laboratories arousability versus GABA modulators Data Blitz Chair: Samer Hattar 11:20 - 11:50 Data blitz by poster presenters Luncheon Seminar Chair: John Renger 12:00 - 12:10 Lunch boxes distributed 12:10 - 12:40 Immunogenetics of narcolepsy Emmanuel Mignot Stanford University 12:40 - 13:10 Break Session 2 - Rhythm & Metabolism Chair: Akhilesh Reddy 13:15 - 13:20 Introductory Remarks Akhilesh Reddy University of Cambridge Bioenergetic regulation during the sleep- 13:20 - 13:50 Joseph T. Bass Northwestern University wake cycle by the molecular clock A new aspect of organ lipids in metabolic 13:50 - 14:20 Hitoshi Shimano University of Tsukuba diseases, lessons from Elovl6 A small-molecule AdipoR agonist for 14:20 - 14:50 Takashi Kadowaki The University of Tokyo type 2 diabetes and short life in obesity Poster Session 15:00 - 16:15 Poster Session (Poster awards presentation begins at 16:05, led by Michael Hastings) Session 3 - Clock Chair: Ravi Allada 16:20 - 16:25 Introductory Remarks Ravi Allada Northwestern University Molecular architecture to the circadian 16:25 - 16:55 Joseph S. Takahashi University of Texas Southwestern Medical Center clock in mammals New cellular regulations of the circadian 16:55 - 17:25 Hitoshi Okamura Kyoto University clock Systems and Synthetic Biology of 17:25 - 17:55 Hiroki R. Ueda The University of Tokyo / RIKEN QBiC mammalian circadian clocks Closing Remarks 17:55 - 18:00 Closing Remarks Masashi Yanagisawa WPI-IIIS, University of Tsukuba Reception / Mixer 18:30 - 21:00 The reception/mixer will commence after a short duration upon the close of the symposium 2 2 Homeodynamics in Clocks, Sleep and Metabolism General Information Wednesday, September 24, 2014 Venue Ito International Research Center 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan Phone : +81-3-5841-0779 (9:00 am - 5:30 pm) E-mail: [email protected] Access information: http://www.u-tokyo.ac.jp/ext01/iirc/en/access.html Hall Layout (Ito Hall B2F) Notes 1. No power outlets are available nearby audience seats 2. Eating and drinking are prohibited in the Ito Hall (except for luncheon seminar period) 3. No smoking on the premises 4. Wireless LAN is available; Network ID: iirc-hall Password: %01-2012-guest Lunchbox Free lunchboxes will be provided for pre-registered participants. Extra may be distributed to non-pre-registered participants on a first-come-first-served basis (will be announced). Mixer (7:00 - 9:00 pm, September 24) Capo PELLICANO 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan Phone : +81-3-5841-1527 *Reception starts at 6:30 pm *We will welcome walk-in participants. Please pay the participation fee in advance (industry 7,000 JPY; academic 5,000 JPY; students 3,000 JPY) at the reception desk of the symposium to receive a ticket. 3 2 Homeodynamics in Clocks, Sleep and Metabolism Session 1 | 9:45 – 10:15 Forward genetic analysis of sleep in ENU-mutagenized mice ABSTRACT Unbiased forward genetic analysis can be a powerful approach to crack open biological black boxes where a meaningful hypothesis is unavailable. The neural substrate for “sleepiness,” as well as its regulatory pathways, remains one such black box in behavioral neuroscience. Although genetic and chemi- cal screening for the sleep/wake phenotype has been intensively carried out in fruit flies and zebra fish, the behavioral readout used in these screens has been the animal’s locomotor activity, a surrogate marker for sleep/wake. We set out to perform a forward genetic screen of sleep/wake traits in ENU-mutagenized mice based on true EEG/EMG-based somnography, the gold standard for sleep assessment in mammals. Through the streamlining of surgical procedures for implanting EEG/EMG electrodes and development Masashi Yanagisawa of semi-automatic sleep staging software that is optimized for genetic screens, we achieved a sustained throughput of 80 mice/week, with each International Institute for mouse sleep-monitored for 5 days. The tight distribution of EEG/EMG- Integrative Sleep Medicine based quantitative parameters for sleep/wake behavior (relative standard (WPI-IIIS), University of deviation of 5-10%) ensured a robust screen, which we expected would yield Tsukuba, Japan a spectrum of mutations distinct from that found in flies. We have so far screened >7,000 heterozygous ENU-mutagenized founders, and established >10 pedigrees exhibiting heritable and specific sleep/wake abnormalities. Linkage analysis in N2 backcrosses between inbred strains highly close to each other (C57BL/6J versus C57BL/6N) ensured no interference from inter-strain phenotypic differences. By combining linkage analysis and the whole-exome deep sequencing, we have so far molecularly identified at least three mutations: Dreamless, causing short and highly fragmented REM sleep; Sleepy-1 and Sleepy-2, each causing a significant hypersomnia (increased non-REM sleep). Genetic, biochemical and neuro- physiological analyses of these mutations are underway. Since these domi- nant mutations cause quite strong phenotypic traits, we expect that the mutat- ed genes are at or nearby the core of the elusive pathway regulating sleep/wake amounts. Co-author: Hiromasa Funato International Institute for Integrative Sleep Medicine (WPI-IIIS) University of Tsukuba, Japan 4 Homeodynamics in Clocks, Sleep and Metabolism Session 1 | 10:15 – 10:45 Neural circuits controlling sleep and wakefulness ABSTRACT The neural circuits controlling sleep and wakefulness are distributed in the basal forebrain/preoptic area, hypothalamus, and brainstem. Each brain region contains a diversity of cell types with intricate synaptic interactions through both local and long-range connections, but the specific roles played by each neuronal type remains unclear. Using optogenetic manipu- lation, behavioral measurements, electrophysiological recording, imaging, and virus tracing, we define the functional properties and connectivity of different cell types in both the basal forebrain and brainstem underlying wake, rapid-eye-movement (REM) sleep, and non-REM sleep. Yang Dan University of California, Berkeley, USA 5 Homeodynamics in Clocks, Sleep and Metabolism Session 1 | 10:45 – 11:15 Orexin/hypocretin receptor antagonist preclinical profile on sleep and arousability versus GABA modulators ABSTRACT Orexin (hypocretin) receptor antagonists (ORAs) promote sleep onset and maintenance by transiently inhibiting wake signaling, a very different mechanism of action from GABAaR modulators which induce sleep through globally inhibiting the CNS via enhancing inhibitory neurotrans- mission. Compounds that increase physiological sleep should preserve the animal’s ability to wake to relevant auditory cues signaling critical infor- mation (salience) while maintaining sleep during ambient (non-salient) noise. Moreover, sleep inducing compounds which cause impairment of cognitive function can be of concern. Here we examine DORA’s and GABAaR modulators for the ability to impair arousability and/or cognitive performance after drug administration. Rhesus monkeys, and dogs, implanted with EEG, EMG and EOG telemetry were assessed for John Renger sleep/wake activity. Stimulus-evoked arousability gating was evaluated by Neuroscience Discovery, conditioning to acoustic stimuli with reward (CS+), or neutral (CS-) tones. Once conditioned, stimuli were presented near T and cognition was Merck Research Laboratories,
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