# Mechanism of sleep regulation by SIK3

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $56,913

## Abstract

Project Summary – PARENT APPLICATION
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:** 10570655
- **Project number:** 3R01NS107969-04S1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** David Menassah Raizen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $56,913
- **Award type:** 3
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10570655

## Citation

> US National Institutes of Health, RePORTER application 10570655, Mechanism of sleep regulation by SIK3 (3R01NS107969-04S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10570655. Licensed CC0.

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