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The role of Salt Inducible Kinases in regulating sleep

Reference	BB/W016486/1
Principal Investigator / Supervisor	Dr Aarti Jagannath
Co-Investigators / Co-Supervisors	Professor Russell Foster, Dr Sridhar Vasudevan, Professor Vladyslav Vyazovskiy
Institution	University of Oxford
Department	Clinical Neurosciences
Funding type	Research
Value (£)	608,164
Status	Current
Type	Research Grant
Start date	01/10/2022
End date	30/09/2025
Duration	36 months

Abstract

The broad aims of this application are to study the role of Salt-Inducible kinases, and their phosphorylation targets, that determine the behavioural states of sleep and wake. Good sleep is a critical determinant of health and disrupted sleep is a direct cause of many chronic conditions that impact healthy ageing, such as Type 2 diabetes, cancer and immune dysfunction. Despite this realisation, our understanding of the genes and molecular substrates that generate and regulate sleep are largely unknown. Recent studies have shown the phosphorylation state of synaptic proteins tracks sleep/wake history, and this relies on Salt-Inducible Kinase family. Our own data show that such phosphorylation can also induce sleep. We hypothesise that the Salt-Inducible Kinase family are a key node of the molecular pathways that regulate sleep, by phosphorylating a core group of synaptic proteins in response to the different drives that regulate sleep. Our approaches will combine in vivo mouse sleep (EEG) and circadian rhythm monitoring, phosphoproteomics and transcriptomics, and electrophysiology. We will use transgenic mice that express catalytically inactive versions of the different SIKs (SIK1/2/3) either alone or in combination to address the following objectives: 1. To determine the contribution of individual members of SIK family in transducing different signals to sleep and circadian rhythm regulation. 2. To understand how each member of SIK family shapes the synaptic phosphoproteome and to identify the minimal changes in this proteome that can induce sleep. 3. To understand how each member of SIK family shapes the synapse and neurophysiology. The programme of work proposed will address a major gap in our knowledge of sleep by identifying the genes and molecular substrates that underpin this critical behaviour.

Summary

Despite the growing appreciation of the fundamental importance of sleep and circadian rhythms across multiple domains of health, our understanding of why we sleep and the molecular mechanisms that underpin this critical behaviour, remain largely unknown. We propose to study the fundamental biology of how sleep is signalled at a molecular, neuronal and behavioural level, to identify the molecular pathways that regulate sleep. In order for sleep to have its restorative effects, synapses - the points at which nerve impulses pass information from one neuron to another - must be remodelled during sleep to encode fresh memories and experiences. Recent transformative research shows that proteins at the synapse are tagged by phosphorylation in a manner that tracks the time spent awake, and that this may underlie the basis of how synapses can be remodelled during sleep. Proteins are phosphorylated by kinases, and we have shown previously that Salt Inducible Kinase 1 regulates circadian rhythms in the brain. Building upon this work, we propose experiments that will investigate the role of the Salt Inducible Kinase (SIK) family on the regulation of synaptic proteins and their role in the regulation of sleep. Our approaches will include monitoring sleep and circadian rhythms in genetically altered mice that express inactive versions of the individual SIKs. The mice will be exposed to challenges that alter sleep and circadian rhythms in different ways. These include sleep deprivation, wake or sleep promoting drugs such as caffeine, or nocturnal light exposure. We will then assess the mice for their resulting sleep and circadian behaviour and protein phosphorylation at the synapse. We will also examine whether the changes in protein phosphorylation affect how information is transmitted at the synapse by recording electrical activity. We predict that the loss of activity of SIKs will impair or enhance certain aspects of protein phosphorylation that are essential for the induction of sleep. Collectively, these experiments will provide an understanding of the key pathways by which sleep is regulated at the molecular level.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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