Masashi Yanagisawa

Toward the mysteries of sleep

Masashi Yanagisawa, MD, PhD
Director and Professor, International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba (Japan)
Adjunct Professor, Molecular Genetics Neuroscience, UT Southwestern Medical Center (United States)

Keynote Summary: Although the executive neurocircuitry and neurochemistry for sleep/wake switching has been increasingly revealed in recent years, the fundamental mechanism for homeostatic regulation of sleep, as well as the neural substrate for “sleepiness” or sleep need, remains unknown. We have initiated a large-scale (>9,000 mice thus far) forward genetic screen of sleep/wake phenotype in ENU-mutagenized mice based on EEG/EMG measurements. By combining linkage analysis, whole-exome sequencing and genome editing, we have identified the causal mutations in several pedigrees with marked sleep abnormalities (Nature 539:378-383, 2016). We expect that the mutated genes will provide new insights into the elusive cellular/molecular pathway regulating sleep. Indeed, through a systematic cross-comparison of the hypersomnia Sleepy mutants and sleep-deprived wildtype mice, we have recently found that the cumulative phosphorylation state of a specific set of mostly synaptic proteins may be the molecular substrate of sleep need (Nature 558:435-439, 2018).

Biosketch: In 1988, as a graduate student at University of Tsukuba, Yanagisawa discovered endothelin, a potent vasoconstrictor peptide from vascular endothelial cells, which sparked an intense research activity in the field; his original paper has been cited >13,000 times by now. In the subsequent year, his group identified a receptor for endothelin, which would become an important drug target; the endothelin receptor antagonist bosentan was approved in 2001 for the treatment of pulmonary hypertension.

He was recruited to University of Texas Southwestern Medical Center at Dallas in 1991 as an HHMI Investigator. In 1996, he initiated a systematic search for endogenous ligands of “orphan” G protein-coupled receptors, which resulted in his 1998 discovery of orexin, a hypothalamic neuropeptide. He then discovered in 1999 that orexin deficiency causes the sleep disorder narcolepsy. This opened up a new avenue in sleep research, leading to better understanding of sleep/wake switching circuitry in the brain. The notion that orexin is an important endogenous waking agent led to the development of orexin receptor antagonists as sleep-inducing drug, first of which, suvorexant, was approved in 2014.

Recognizing, however, that the fundamental mechanism for sleep homeostasis still remains a mystery, in 2010 he embarked upon a highly ambitious project of polysomnography (EEG/EMG)-based forward genetic screen for sleep/wake abnormalities in chemically mutagenized mouse cohort. This large-scale project is now continuing at the International Institute for Integrative Sleep Medicine (WPI-IIIS) in Tsukuba, Japan, and has recently led to identification of several new genes that are importantly involved in the regulation of sleep amounts and the level of sleep need.

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