Role of mTOR in Circadian and Sleep Deregulation in Smith-Kingsmore Syndrome (SKS) - ABSTRACT Smith-Kingsmore Syndrome (SKS) is a newly discovered genetic disorder caused by mutations in the mechanistic target of rapamycin (MTOR) gene. MTOR functions to coordinate intracellular energy levels with cellular homeostasis and growth. MTOR deregulation is implicated in various pathological conditions, including brain dysfunction. A notable example is tuberous sclerosis, in which MTOR hyperactivation due to Tsc1/2 mutation causes autism, epilepsy, and benign tumors in the brain. Clinical features of SKS include macrocephaly, epilepsy, seizure, intellectual disability, autism spectrum disorder, and developmental delay. Our recent studies also revealed new aspects of SKS, including sleep/wake disruption, hyperphagia, hyperactivity, and self-aggression, all indicative of homeostatic imbalance and hypothalamic dysfunction. Our research has a central focus on the circadian and sleep systems. Sleep/wake disturbance is prevalent in SKS patients and represents a top concern of patients and caregivers. Sleep insufficiency reflects homeostatic imbalance in the brain, exacerbating disease states. Our long-term goal is to advance the understanding of the pathophysiology and mechanisms of SKS. Our central hypothesis is that chronic activation of MTOR in SKS disrupts cell physiological homeostatic, leading to disruption of sleep/wake and other functions. To test this hypothesis, we will generate cellular and mouse SKS models and investigate how the pathogenic SKS variants affect MTOR activity, circadian rhythms, sleep/wake homeostasis, and other behavioral and cognitive functions. We hope to provide proof of principle that a better understanding of causal mechanisms, beyond genotype, enables precision medicine treatment strategies. The MTOR inhibitor rapamycin impacts both sleep time/phase and quality. Notably, low-dose rapamycin, optimized for specific alleles to normalize MTOR activity, was able to restore the patient’s sleep/wake pattern, while improving other clinical features. We will explore rapamycin regimens and test the hypothesis that by normalizing MTOR activity, allele-specific low-dose rapamycin can improve sleep/wake and other functions. As rapamycin impacts sleep time and quality and other behavioral and cognitive functions, we hope to expand the concept that sleep/wake function represents a novel neurophysiological biomarker for rapamycin dosing, MTOR activity and CNS homeostasis. This research will lay the groundwork for future mechanistic and therapeutic research. Further, this research has direct and broader implications for other MTORopathies including TSC.