Mechanism of Sleep Regulation by SIK3

Project Summary Sleep and metabolic disorders are often comorbid, but how they interact is poorly understood. The salt inducible kinase SIK3 was identified (first in C. elegans and 8 years later in flies and mice) as a sleep drive regulator. Our findings suggest that SIKs connect sleep and metabolic regulation. In the prior funding cycle, we demonstrated hierarchical somatic/neural interactions regulating both sleep and energy homeostasis. We have shown that the sleep and energy-regulating roles of KIN-29/SIK occur by inhibiting the class 2 histone deacetylase HDA-4 (HDAC4) in 12 pairs of glutamatergic neurons. Illuminating the mechanism by which KIN- 29 signals in glutamatergic neurons during high sleep drive will be the goal of aim 1. We will study the role of CREB and CREB-regulated transcription coactivator 1 (CRTC1) in glutamatergic neurons. In aim 2, we will test the hypothesis that reactive oxygen species promote sleep. In aim 3 we will test the hypothesis that NAD+ precursors promote sleep and are reduced in kin-29 mutants. Finally, in aim 4, we will identify genes whose expression is regulated by the KIN-29--|HDA-4 signaling module. Such genes will be candidates for mediating sleep-promoting signaling by glutamatergic neurons. At the completion of these aims, we will have an improved understanding of the genetic and metabolic regulation of sleep. Data collected in aim 4 will motivate additional genetic hypotheses that will be tested in future research.