Investigating the molecular mechanisms underlying sleep disruption in Smith-Kingsmore Syndrome

/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. Project Number: 1F31NS147396-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Curtis Carlson | Institution: UNIVERSITY OF CALIFORNIA AT DAVIS, DAVIS, CA | Award Amount: $43,471 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F01B-D (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11311599