Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY Sleep has often been considered a behavior in which a subset of neurons dictates to peripheral tissues in a top-down fashion. Recent work has demonstrated that this is a gross oversimplification in that bottom-up signals from fat cells, muscle, and glia can affect sleep-promoting neuron function as well. Communication between sleep-promoting circuitry and metabolic tissues is especially important in that it gives sleep-promoting circuits information about the organism’s global energy state. Lapses in this communication, underly sleep disturbances and increase an organism’s likelihood of developing metabolic disorders such as obesity and insulin resistance. Our findings in the C. elegans model organism that meets all the behavioral hallmarks of sleep and utilizes similar genetic pathways to regulate sleep and fat metabolism, suggest that salt-inducible kinases (SIKs) connect sleep and metabolic regulation. Loss of the SIK3 homolog in C. elegans called KIN-29 in 12 pairs of glutamatergic neurons result in sleepless and adipose animals. Inducing fat breakdown in kin-29 mutants restored the sleep and fat store changes in these mutant animals. Moreover, inhibition of mitochondrial beta-oxidation of fatty acids, which reduces reactive oxygen species (ROS) production, reduced sleep. The goal of this proposal is to test the hypothesis that kin-29/SIK3 signaling utilizes ROS accumulation from fat breakdown as a sleep pressure signal in the metabolic regulation of sleep. Consistent with this hypothesis, kin-29 mutant animals have low baseline levels of ROS. Moreover, preliminary global proteomic analyses show that several antioxidant proteins such as superoxide dismutase (SOD) proteins are upregulated in kin-29 mutants, while mutants that remove mitochondrial SOD-2/3 function that are unable to detoxify ROS enhance sleep. Aim 1 will test the hypothesis that ROS from fat breakdown restores the low ROS levels of kin- 29 and hence its sleep phenotype. I will test the dynamics of ROS during sleep and wake in kin-29 mutants as well as in sleep-deprived wild-type worms, and test whether genetically inducing fat breakdown in the adipose and sleepless kin-29 mutant will restore the reduced ROS phenotype of kin-29 mutants. Aim 2 will test the hypothesis that mitochondrial ROS production restores sleep in kin-29 mutants and requires the sleep- promoting neurons in C. elegans. To do so, I will use in vivo optogenetic ROS-generation tools combined with genetic sleep-defective mutants. Collectively, the proposed work will elucidate the mechanisms by which global energy state is communicated to sleep circuits. Findings from this work will also guide future therapeutic approaches in disorders of sleep regulation that frequently occur in individuals with disorders of metabolism.
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