# Molecular, cellular and physiological mechanisms of the mammalian circadian clock

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $530,904

## Abstract

PROJECT SUMMARY/ABSTRACT
The circadian clock regulates many aspects of physiology and behavior. These rhythms are
coordinated by the master clock in the suprachiasmatic nuclei (SCN) of the hypothalamus. This
core clock is composed of a transcriptional/translational negative feedback loop, where
transcriptional activators BMAL1/CLOCK regulate the expression of their own repressors, the
PER and CRY proteins. This repression step is critical, as without it, there's no rhythm. The key
step in the repression process is coordinated translocation of the PER/CRY protein complex
from the cytoplasm to the nucleus. Recently, we've found that the same NRON complex that
regulates translocation of the NFAT pathway, also regulates the translocation of the PER/CRY
complex and circadian clock function. The NFAT pathway regulates development but also innate
and adaptive immunity in the periphery and the central nervous system. This NRON complex is
comprised of signaling molecules, e.g. CSNK1e, GSK3B, and DYRK1 (known clock kinases), but
also scaffolding (IQGAP1, the ncRNA NRON), proteolysis (PSMD11, CUL4B, UREB1), and
nuclear translocation (KPNB1, CSE1L, TNPO1). Using genetics in human cells and in
Drosophila, we've shown that most of these components alter period length or are required for
clock function altogether (KPNB1, PSMD11). Further, pharmacological perturbation of the
NFAT pathway alters SCN physiology and circadian function. Here, we seek to better
understand this key repression step by understanding its biochemical and cell biological
mechanisms, study the cross talk between the two pathways in the SCN, and generate a suite of
genetic models to characterize the role of these genes in modulating the SCN clock and the
sleep/wake cycle. This work will provide the first broad linkage between NFAT-regulated cell
and physiological processes including immunity in the brain and core clock function that
governs behavior and associated physiologies.

## Key facts

- **NIH application ID:** 10462479
- **Project number:** 5R01NS054794-16
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** JOHN B HOGENESCH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $530,904
- **Award type:** 5
- **Project period:** 2007-05-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10462479

## Citation

> US National Institutes of Health, RePORTER application 10462479, Molecular, cellular and physiological mechanisms of the mammalian circadian clock (5R01NS054794-16). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10462479. Licensed CC0.

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