The Inaugural International Symposium on
Aging Research (ISAR)　

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. In the subsequent year, his group identified a G protein-coupled 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. After moving to University of Texas Southwestern Medical Center in 1991 as a young HHMI Investigator, he identified the endothelin-converting enzyme, a metalloprotease that generate the active, mature endothelin peptides. Through gene-targeting experiments in mice, he also discovered in 1994 that the endothelin pathway is essential for embryonic development of certain neural crest derived tissues, and that endothelin-B receptor deficiency causes Hirschsprung disease in mice and humans. 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, and led to a better understanding of sleep/wake switching mechanisms 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 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. Since one of these mutant strains, Sleepy, carried a gain-of-function allele in the serine/threonine kinase Sik3, Yanagisawa systematically compared the phospho-proteomic states of Sleepy and sleep-deprived mouse brains in collaboration with Qinghua Liu. This effort has led to the hypothesis that cumulative phosphorylation and dephosphorylation of a specific subset of mostly synaptic proteins may underlie accumulation and dissipation of sleep need, thus representing the mysterious molecular substrate for “sleepiness.”