# The Circadian Molecular Clock is a Biomarker for Epilepsy in Focal Cortical Dysplasia

> **NIH NIH R01** · BROWN UNIVERSITY · 2021 · $77,206

## Abstract

Abstract
 Focal epilepsy is the most common cause of epilepsy. The abnormal epileptogenic
region of the brain that generates seizures or "seizure focus" is critically important because its
removal often results in a complete cure of the epilepsy. However, this tissue is under studied.
Our first transcriptome study demonstrated diminished expression of the CLOCK transcription
factor in seizure focus in contrast to control tissue. In addition, the downstream targets of
CLOCK, the PAR bZip transcriptions factors are also diminished in the seizure focus. The
deletion of Par bZip transcription factors in mice causes epilepsy. Thus, the role of CLOCK in
the seizure focus may be through its regulation of the Par bZip transcription factors.
 In our study of CLOCK, we find that the deletion of CLOCK changes synaptic numbers,
especially in inhibitory synapses. However, the function of PAR bZip factors per se in
synaptogenesis and synaptic maintenance has not been explored, despite reports of their roles
in regulating neurotransmitter levels. Based on our published finding that increased neuronal
hyperexcitability of CLOCK-deficient mutants is associated with changes in the number of
inhibitory synaptic terminals on excitatory pyramidal neurons, we hypothesize that these
changes are mediated by PAR bZip. The Aims of this Supplement will test the hypothesis that,
as downstream effectors of CLOCK, PAR bZip transcription factors govern synaptic
maintenance and stability (Aim 1), as well as the expression levels of synaptic proteins (Aim 2).
Both Aims will utilize the triple PAR bZip knockout mouse, so that Sean will gain experience in
histological techniques and advanced microscopy, as well as molecular analyses and
bioinformatics.

## Key facts

- **NIH application ID:** 10351603
- **Project number:** 3R01NS104428-03S2
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Judy Shih-Hwa Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $77,206
- **Award type:** 3
- **Project period:** 2021-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10351603

## Citation

> US National Institutes of Health, RePORTER application 10351603, The Circadian Molecular Clock is a Biomarker for Epilepsy in Focal Cortical Dysplasia (3R01NS104428-03S2). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10351603. Licensed CC0.

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