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Understanding the interaction between sleep and SHANK3/B-catenin signaling in Autism

Award Number: R56NS124805
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Understanding the interaction between sleep and SHANK3/B-catenin signaling in Autism - PROJECT SUMMARY Sleep problems occur at a higher rate in Autism Spectrum Disorder (ASD) than in typical development. Problems falling asleep predict severity of ASD core symptoms and associated problem behaviors, and lead to chronic sleep deprivation (SD). Understanding the effects of sleep deprivation is important because it adversely affects cognition, attention and emotional regulation. Nonetheless, little is known about the mechanisms responsible for abnormal sleep or the consequences of chronic sleep loss in ASD. Identifying these mechanisms may lead to new interventions that will improve quality of life of patients and their families. The study of genetic syndromes with high rate of ASD diagnosis has provided important clues into mechanisms. One such syndrome is Phelan McDermid Syndrome (PMS), characterized by deletions in the SHANK3 gene. Mutations in SHANK3 are also often found in patients with idiopathic ASD. We previously showed that the ASD sleep phenotype is recapitulated in mice with a C-terminal deletion in Shank3 (Shank3∆C), which struggle to fall asleep despite being sleepy (i.e. after SD). We also showed that SD induces greater number of differences in gene expression in Shank3∆C animals than WT. Therefore, we hypothesize that Shank3∆C animals display an abnormal transcriptional response to SD. The objective of this proposal is to identify the mechanisms that underlie the abnormal response to SD in ASD, using Shank3 mutant mice as a model. Our preliminary studies show that SD increases the nuclear localization of full-length SHANK3a, an isoform that is absent in Shank3∆C animals and thought to be primarily synaptic. SHANK3 binds b-catenin. Translocation of β-catenin into the nucleus regulates transcription through chromatin remodeling and is key to many developmental processes. Our preliminary studies show that SD produces changes in chromatin topology in glutamatergic neurons, and that some of these changes do not take place in Shank3∆C animals. Therefore, our central hypothesis is that SD changes chromatin topology and gene expression by increasing nuclear SHANK3a and b-catenin and that the absence of SHANK3a in Shank3∆C interferes with this process. To test our hypothesis, in Aim 1, we will first determine the effects of SD in SHANK3a/b-catenin synaptic-nuclear signaling. Then, in Aim 2, we will determine the effect of SD in SHANK3-dependent chromatin topology and transcription at single-nuclear resolution. We will examine two brain regions important to ASD and impacted by sleep loss: pre-frontal cortex and hippocampus. We will subsequently test candidates prioritized through omic studies for their ability to influence sleep. Completion of these aims will allow us to determine how sleep interacts with SHANK3 and β-catenin to regulate chromatin and gene expression.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2022	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/19/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $497,916 )
2022	2022	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/15/2022	NEW	$497,916
														Subtotal = $497,916

Grand Total All Awards = $497,916

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Understanding the interaction between sleep and SHANK3/B-catenin signaling in Autism

Award Number: R56NS124805

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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