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About IIIS

CORE RESEARCH GROUP

Masashi Yanagisawa / Hiromasa Funato Lab

In order to crack open the black box of sleep/wake control, Dr. Yanagisawa and Dr. Funato’s laboratory is engaged in a highly ambitious project aiming at forward genetic analysis of randomly mutagenized mice for sleep abnormalities. They have so far screened >5,000 mice and identified a dozen pedigrees with heritable sleep abnormalities. Causative gene mutations will soon be identified in these pedigrees by chromosomal mapping and next-generation DNA sequencing. Those genes will reveal a central pathway for the regulation of sleep. Another approach they are actively pursuing is to develop small molecule agonists for the orexin receptor. These compounds will not only be indispensable chemical tools to manipulate sleep and wakefulness in experimental animals, but also become candidates of a novel drug for the mechanistic treatment of narcolepsy and other conditions with excessive sleepiness.

Takeshi Sakurai Lab

Dr. Sakurai, well-noted for his research on arousal control mechanisms and discovery of the neuropeptide orexin with current IIIS director, Masashi Yanagisawa (Sakurai, et al. Cell 1998, which presently exceeds 3000 citations), is additionally interested in circadian rhythm-associated behaviors including eating, emotions and general social interactions. Currently, his laboratory’s research topics include the following: 1. Elucidation of sleep-wake controlling mechanisms, 2. Mechanisms behind narcoleptic and cataplectic attacks. Besides the above, his group is actively involved in joint research projects with other laboratory members.

Yoshihiro Urade Lab

Dr. Urade’s laboratory is investigating molecular mechanisms of sleep-wake regulation by endogenous sleep-promoting substances, such as prostaglandin D2 and adenosine. His research group established the sleep bioassay system to monitor the electroencephalogram, electromyogram and locomotor activity of various gene-manipulated animals under a freely moving condition. If necessary, they can infuse drugs into the cerebrospinal fluid space, stimulate the target nucleus in the brain, and record the neural activity of a certain nucleus of freely-moving animals. By using these systems, his group identified the sleep centers in the ventrolateral preoptic area and the nucleus accumbens shell, and revealed the neuronal circuit between the sleep centers and various arousal centers. Combined with modern gene-manipulation and neuroscience technologies, they attempt to clarify more precisely the molecular mechanism and neural circuits of sleep-wake regulation. Their research is also useful to improve our daily sleep and the quality of life by controlling our innate sleep-wake regulatory system.

Robert Greene Lab

Slow wave activity (SWA) power expressed during slow wave sleep (SWS) increases proportionally with prior waking duration and decays during SWS. This large circuit phenomena is the most robust index of sleep need currently available, yet little is known about the local circuit and cellular activities that are responsible for its generation. Further, it has been proposed that the up states occurring during SWS are electrophysiologically identical to stabilized up state membrane potentials during waking (W) and that SWA reflects a destabilized up state, but this has not been rigorously investigated. Dr. Greene’s research group plans to employ whole cell patch clamp recordings of cortical, pyramidal cells and interneurons acquired in vivo in un-anesthetized rodents during W and SWS, in conjunction with local field recordings, imaging of intracellular free calcium concentration and optogenetically controlled activation of distinct morphological subsets of interneurons to investigate the local network and cellular mechanisms involved in SWA generation.

Qinghua Liu Lab

Sleep is essential for normal brain functions and viability in mammals, however, the molecular circuits of sleep regulation remain a fundamental mystery in modern biology. Dr. Liu’s research group will integrate biochemical, chemical biology, and genetic approaches to identify key genes in sleep/wake regulation in mice: 1) They will use the state-of-the-art quantitative mass spectrometry (e.g. SILAC) to compare brain proteome between wild type and sleep mutant mice, isolated from a forward genetic screen, to identify candidate sleep regulatory genes; 2) They will develop a novel and rapid technology for adult- and brain-specific knockdown (or knockout) of candidate genes to investigate their functions in sleep/wake regulation; 3) They will conduct in vivo screening of natural or synthetic small molecules to identify sleep-promoting compounds. Together, these multi-disciplinary studies will uncover novel mechanism of sleep regulation and develop novel sleep medicine.

Hiroshi Nagase Lab

The target compounds of Dr. Nagase’s laboratory research are orexin receptor agonists. His research group has already succeeded to design and synthesize highly potent and selective small molecules for the orexin 2 receptor. One of the compounds, YN-1055 is the first and most selective non-peptide for the orexin 2 receptor (EC50= 20nM) in the world. They are now trying to improve the activity and selectivity for the orexin 2 receptor and also obtain the orexin 1 or mixed agonist for orexin 1 and 2 receptors. They are also interested in opioid receptor type and subtype selective ligands which have no morphine-like side effects (i.e. addiction, constipation and respiratory depression) and also aversive effects such as the psychotomimetic effect, which U-50488H (Upjohn-type κ agonist) has. They have already obtained a selective κ agonist, nalfurafine (TRK-820) which has no addiction and aversion and was released as an antipruritic agent for kidney dialysis patients in 2009. Now they are trying to modify the compound to improve the analgesic effect to apply it to cancer patients.

Masanori Sakaguchi Lab

After receiving his medical degree from the University of Tsukuba in 2001, Dr. Sakaguchi continued to pursue a research-oriented career in neuroscience, focusing on regenerative medicine, adult neurogenesis and memory in particular. His experience abroad and career thereafter provided him with a firm grasp of world-class techniques (optogenetics, neuronal tracing, behavioral neuroscience, etc.) but furthermore, with an open-mindedness in understanding both Western and Eastern cultures and sufficient communication abilities (fluent English and intermediate-level Chinese) all so vital in scientific research today. Currently, at IIIS his research group strives to investigate the relation between sleep and memory. They hope to clarify the still unanswered questions regarding narcoleptic and cataplectic attacks, neuronal networks possibly involved in sleep-wake transitions as well as the further elucidation of sleep stages and their significance towards memory consolidation.

Michael Lazarus Lab

Dr. Lazarus and his research group are interested in the role of adenosine in sleep-wake regulation. In particular, adenosine A2A receptors are densely expressed on striatopallidal neurons of the basal ganglia, where dopamine D2 receptors are co-expressed with A2A receptors and involved in motor function, habit formation, and reward/addictive behaviors. They want to know the extent to which A2A and D2 receptors in the basal ganglia contribute to the regulation of sleep and waking. They have recently shown that caffeine induces wakefulness by blocking the action of adenosine on A2A receptors in the nucleus accumbens indicating that the nucleus accumbens is a core structural element for the control of sleep and wakefulness within the basal ganglia. These findings further suggest the intriguing possibility that the motivational state may be an important fundamental regulator of sleep and wake (Lazarus et al., Trends Neurosci, doi: 10.1016/j.tins.2012.07.001).

Yu Hayashi Lab

Sleep in mammals has evolved into a complex phenomenon composed of two distinct states, REM (rapid eye movement) sleep and non-REM sleep. REM sleep is the major source of dreams, whereas non-REM sleep is characterized by a synchronous brain activity called slow waves. Little is known, however, about the evolutionary origin or individual roles of these two sleep states. Dr. Hayashi’s laboratory will address these questions through identification and manipulation of the neurons that function as the REM/non-REM sleep switch using mice. While REM and non-REM sleep are unique to certain vertebrate species, sleep itself is a widely conserved phenomenon. The nematode Caenorhabditis elegans, with its genetic accessibility and well-defined neural circuit, is a powerful means for neuroscience research. Therefore, his laboratory also aims to elucidate widely conserved molecular mechanisms underlying sleep using C. elegans.

University of Tsukuba Collaborative Research Group

Ichiyo Matsuzaki Lab

As a specialist in space medicine and industrial psychiatry, Dr. Matsuzaki has extensively contributed to industrial hygiene and mental health support activities, including sleep monitoring, in a number of private enterprises and national/local public bodies. His research in the field of space medicine has crossed into astronaut selection and training as well as in mental care for astronauts during stays in the International Space Station, made possible by his position as Senior Researcher of the Japan Aerospace Exploration Agency (JAXA). His research aims serve a practical macro policy-making agenda, with achievements woven into a “Comprehensive Mental Health Support System from Primary to Tertiary Prevention” using knowledge management methodology where practical and scientific information are combined.

Hitoshi Shimano Lab

Dr. Hitoshi Shimano is engaged in research dealing with the energy sensing system of starvation and satiety in vivo and unknown roles of tissue fatty acids for cellular physiological and pathological signals through energy transcription factors such as SREBP. His work has been known worldwide and highly praised for its uniqueness and originality, for instance, showing that modification of tissue fatty acid by an enzyme Elovl6 could be a new strategy for obesity–related disorders (insulin resistance, atherosclerosis, and steato-hepatitis) without amelioration of obesity. The research findings and concept are deeply involved in a wide variety of diseases including not only metabolic diseases such as diabetes, dyslipidemia, and cardiovascular diseases, but also chronic inflammatory diseases and even cancers. His lab has recently been attempting to reveal novel functions of tissue fatty acids that might help the understanding of broader biology including brain and mental function and disorders linking to sleep and life-related diseases.

Junichi Hayashi / Kazuto Nakada Lab

Dr. Junichi Hayashi has been studying mitochondrial DNA (mtDNA) for more than 20 years which is located in the mitochondria, the energy factories of the cell. He provided the first evidence that deleted mtDNA found in the cells from patients with mitochondrial diseases causes mitochodrial malfunction using intercellular mtDNA transfer technology which Hayashi and his colleagues developed. Recently, he and Dr. Kazuto Nakada have been engaged in research with experimental data showing that a specific mtDNA mutation which results in overproducing reactive oxygen species can be responsible for the metastasis, diabetes, and B-cell lymphoma development. Their continued effort to elucidate the mechanism of paternal mtDNA elimination led to a surprising finding that innate immune systems can recognize and exclude the cells with very small changes in mtDNA, resulting in the exclusion of the cells with the mutated mtDNA from mice.

Akiyoshi Fukamizu Lab

Biological homeostasis is regulated by a series of chemical reactions in response to external and environmental stimulus. A variety of signals through the plasma membrane are integrated into the nucleus, where histones and transcription factors are modified by phosphorylation, acetylation, ubiquitination, and methylation that are catalyzed by modification enzymes, thereby controlling gene expression. In the laboratory of Dr. Akiyoshi Fukamizu, researchers aim to understand the molecular mechanisms of life style-related and pregnancy-associated diseases, how nutritional and stress conditions regulate epigenomic functions, by using the genetic techniques with animal models such as mice. Pregnancy is a normal physiological process that requires the synchronized adaptation of multiple organ systems. Dysregulation of these homeostatic controls during pregnancy can lead to serious disorders, such as hypertensive disorders, which Dr. Fukamizu and his colleagues are also actively researching.

Satoru Takahashi Lab

Dr. Satoru Takahashi has been focused on the mechanisms of formation of diseased and normal tissues by changes in gene expression and function. To further elucidate the relation between disease genes and morphological phenotypes, he has adopted the use of genetically manipulated mice. Particularly he generated various genetically manipulated mice for the GATA transcription factors that are expressed in the hematopoietic system, to find out at the nucleotide sequence level that GATA-1 is required for the differentiation of erythrocytes, megakaryocytes, eosinocytes, and mast cells, and that more than one regulatory sequence is needed for the control of their expression. His laboratory has started investigating yet less noted large Maf transcription factors. Large Maf transcription factors were originally identified in Japan, but their function in the body and their possible involvement in diseases were unknown at that time. Dr. Takahashi’s laboratory has been generating genetically manipulated mice for 4 large Maf transcription factors that are conserved in humans and mice.

SATELLITE

Tetsuo Shimizu / Takashi Kanbayashi Lab (School of Medicine, Akita University)

The department of Dr. Tetsuo Shimizu and Dr. Takashi Kanbayashi is one of the international clinical research centers on sleep disorders, especially on those with excessive daytime sleepiness such as narcolepsy. Their laboratory analyzes CSF samples of over a thousand patients with excessive daytime sleepiness from all over the world. Measurements of various peptides in CSF such as orexin, MCH, QRFP, etc., are ongoing. In collaboration with several other institutes, they and their researchers evaluate CSF histamine and several autoimmune antibodies such as anti- aquaporin-4 (AQP4) and anti-NMDA receptor antibodies. They have proposed that CSF orexin might be a trait marker and histamine might serve as a state marker of narcolepsy. Recently, through their research, some patients were discovered with symptomatic narcolepsy that had the anti-AQP4 antibody and also low levels of CSF orexin. This may be the first direct evidence indicating symptomatic narcolepsy caused by the autoimmune process.

Carla Green Lab(University of Texas Southwestern Medical Center)

Dr. Carla Green has long been interested in circadian biology. She has identified a number of circadian clock-controlled genes, including a novel rhythmic gene Nocturnin, in the Xenopus retina. Her own laboratory continued to use that model system to study molecular mechanisms of retinal clock function, developing tools to perturb clock function molecularly in transgenic Xenopus. She also continued her studies on the Nocturnin gene and demonstrated that this gene encodes a deadenylase – a polyA-specific ribonuclease that removes the polyA tails from mRNAs. More recently, her laboratory has begun to focus entirely on mammalian model systems and has continued to focus on Nocturnin and its role in clock control of metabolism. The Green research group also works on the role of the Cryptochrome proteins in the central circadian mechanism and on circadian mechanisms of post-transcriptional control. Her laboratory is currently extending these studies to examine post-transcriptional regulatory mechanisms that contribute to neuronal function during sleep.

Joseph Takahashi Lab(University of Texas Southwestern Medical Center)

Dr. Joseph S. Takahashi has pioneered the use of forward genetic approaches for the discovery of genes regulating behavior in the mouse. His work has had broad impact in the fields of neuroscience, genetics and molecular biology. Using a phenotype-driven mutagenesis strategy, Takahashi isolated the first circadian rhythm mutant in the mouse (named Clock). Three years later in a tour de force, Takahashi identified the Clock gene by a combination of transgenic “rescue” and positional cloning. These landmark experiments revealed that the Clock gene encoded a novel member of the basic-helix-loop-helix – PAS family of transcription factors. The cloning of Clock provided an important molecular entrée into the circadian mechanism of mammals and formed the foundation for describing the molecular mechanism of the circadian clock as a transcription-based feedback loop. This initial work was rapidly followed by the discovery of additional core circadian genes over the next three years and led to a description of a conserved clock mechanism in animals. Recently, Takahashi and his colleagues have determined the crystal structure of the CLOCK:BMAL1 transcriptional activator complex and have identified the genomic targets of the core circadian transcriptional regulators throughout the genome.

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