# Circadian and Sleep Programming in Angelman Syndrome Mouse Models

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2020 · $268,885

## Abstract

Project Summary/Abstract:
 Circadian (daily) rhythms regulate myriad behavioral and molecular processes including locomotor activity,
sleep timing, feeding behavior, metabolism, and gene expression. These biological "clocks" are a crucial
component of human health, and improper functioning of this system is associated with sleep/wake disorders,
metabolic syndrome, and obesity. The current molecular model for the circadian clock mechanism comprises
autoregulatory transcriptional & translational feedback loops of central clock genes that necessitate rhythmic
synthesis and degradation of clock gene products. We have found that the effective gene dosage of the Ube3a
gene that encodes an ubiquitin ligase (involved in protein degradation) regulates fundamental properties of the
circadian clock system in mammals.
 The expression level of the Ube3a gene is crucial for normal neurodevelopment. For example, reduced
dosage of Ube3a leads to Angelman Syndrome (AS) and increased dosage/activity can result in autism.
Therefore, the level of expression of Ube3a is critical for normal cognitive development, and the thesis of this
project is that balanced expression of Ube3a is key for stable circadian rhythmicity as well. AS is a disorder
characterized by cognitive/developmental delays, speech impairment, sleep disorders, and seizures. The
paternal allele of Ube3a is imprinted (silenced) in neurons, and most cases of AS result from a deletion of the
maternal Ube3a allele that further downregulates Ube3a in neurons. Mouse models have been generated that
have (i) a deletion of the maternal Ube3a allele (model of AS), and (ii) extra copies of Ube3a (model of autism);
these models enable tests of our hypothesis, which is that Ube3a expression affects the plasticity of circadian
rhythms and that environmental, genetic, and/or pharmacological treatments can be identified that compensate
for the loss of Ube3a expression. This hypothesis will be tested by manipulating environmental, genetic, and
developmental conditions to affect the circadian system in mouse models of AS. Specific pharmacological
treatments will be tested for their potential in reversing the circadian phenotypes of AS models to use as a
basis for identifying a biomarker to be used with human subjects. Clock proteins will be identified as molecular
targets of Ube3a-mediated ubiquitination. Finally, an Ube3a overexpressing mouse model will be tested to
determine if Ube3a overexpression has reciprocal effects to the Ube3a null of AS models.
 This project represents a novel area of investigation that has the potential to enhance health-related
research; its overall significance is (i) to elucidate the role of ubiquitination and imprinting in the circadian
mechanism, and (ii) to identify treatments that ameliorate the circadian disorders of Ube3a imprinting in mouse
models. The answers to these questions will help us to understand fundamental circadian organization and
plasticity in this fascinating–and pot...

## Key facts

- **NIH application ID:** 10005495
- **Project number:** 5R01NS104497-04
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** CARL Hirschie JOHNSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $268,885
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10005495

## Citation

> US National Institutes of Health, RePORTER application 10005495, Circadian and Sleep Programming in Angelman Syndrome Mouse Models (5R01NS104497-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10005495. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*