# Mechanism of sleep regulation by SIK3

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $322,446

## Abstract

PROJECT SUMMARY/ABSTRACT
The high prevalence of coexistent sleep and metabolic disorders suggest that these processes are integrated
at the molecular level, but mechanisms of this integration are unknown. The recent finding that the AMPK
family member SIK3 is a phylogenetically conserved sleep drive regulator combined with our preliminary data
showing both reduced sleep and elevated energy stores in animals mutant for the C. elegans SIK homolog kin-
29, suggests that SIKs are key nodes connecting sleep and energy homeostasis. The model motivating this
proposal is that SIKs are responsive to the energy level in particular neurons; low energy (i.e. low ATP
levels) result in the movement of SIK into the nucleus where, via phosphorylation of a class II HDAC it
de-represses genes that signal to promote sleep and energy reserve mobilization. We will test this model
using the nematode Caenorhabditis elegans and with the following hypotheses: (1) Cellular energy charge is
lower under conditions of increased sleep drive. (2) KIN-29/SIK signals under conditions of low energy to
mobilize energy stores and restore cellular ATP levels and sleep. (3) KIN-29/SIK functions acutely in
metabolically-responsive sensory neurons that regulate the sleep-inducing ALA and RIS neurons; It functions
in the same neurons to regulate fat stores. (4) KIN-29/SIK sleep-promoting activity is controlled by nuclear
import, which is regulated by the upstream kinases LKB1 and PKA. Finally, (5) we will pursue an exploratory
aim by performing a pilot genetic screen to discover new genes that are required for the reduced sleep
phenotype of kin-29 mutants. Experiments in aims 1-4 will illuminate the molecular and cellular mechanism by
which SIKs function to regulate animal sleep and energetic stores. Aim 5, in which we will identify new sleep
genes, will provide a bridge into the next set of hypotheses regarding mechanisms of sleepiness. Lessons
gained from the nematode can motivate focused experiments in mammals, and will inform our understanding
of patients with disorders of sleep regulation.

## Key facts

- **NIH application ID:** 10145816
- **Project number:** 5R01NS107969-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** David Menassah Raizen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $322,446
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145816

## Citation

> US National Institutes of Health, RePORTER application 10145816, Mechanism of sleep regulation by SIK3 (5R01NS107969-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10145816. Licensed CC0.

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