Investigating the molecular mechanisms underlying sleep disruption in smith-kingsmore syndrome

The National Institute of Neurological Disorders and Stroke awarded the University of California, Davis $129,261 on July 21, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to investigate the molecular mechanisms underlying sleep disruption in Smith-Kingsmore Syndrome.

The research develops Drosophila melanogaster animal models of Smith-Kingsmore Syndrome (SKS), a genetic disorder caused by gain-of-function mutations in the mechanistic target of rapamycin gene that produces sleep disruptions, intellectual disability, developmental delay, megalencephaly, seizures, and hyperphagia in patients. Sleep disruption resolution ranks as a top priority for patient caregivers. The project establishes MTOR SKS fly lines using CRISPR technology to complement existing transgenic flies and assay MTOR activity of SKS variants in vivo. The work assesses the impact of MTOR SKS variants on circadian and sleep behaviors, correlating behavioral consequences to alterations of the molecular clock. The research tests whether MTOR SKS variants disrupt mitochondrial homeostasis in neurons and glia, resulting in altered circadian and sleep behavior. The project establishes animal models to delineate genotype-phenotype relationships underlying MTOR SKS variants and determine how they produce sleep disruptions.

Performance takes place in Davis, California, with a period of performance from July 21, 2026, through November 30, 2029.

Abstract

Smith-kingsmore syndrome (SKS) is a recently discovered human genetic disorder caused by gain-of-function mutations in the mechanistic target of rapamycin (MTOR) gene. SKS patients exhibit variable symptoms, including sleep disruptions, intellectual disability, developmental delay, megalencephaly, seizures, and hyperphagia. Resolving sleep disruptions have been identified as one of the top priorities of patient caregivers. To date, most mtorsks variants remain as variants of uncertain significance due to a dearth of cellular and animal models for functional analysis. The overall goal of my project is to develop drosophila melanogaster models of SKS and use these animal models to investigate the behavioral and biochemical consequences of mtorsks variants. In aim 1, I will establish mtorsks fly lines using crispr to complement existing transgenic flies already developed in my lab and assay MTOR activity of SKS variants in vivo. In aim 2, I will assess the impact of mtorsks on circadian and sleep behaviors and correlate behavioral consequences to alterations of the molecular clock. Finally, in aim 3, I will test the hypothesis that mtorsks disrupt mitochondrial homeostasis in neurons and glia, resulting in altered circadian and sleep behavior. My project will establish urgently needed SKS animal models to delineate genotype-phenotype relationships underlying mtorsks variants and sleep disruptions.