# Molecular mechanisms of mammalian circadian clock function - Renewal - 1

> **NIH NIH R35** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $644,919

## Abstract

Abstract
Circadian clocks throughout the body drive rhythmic expression of thousands of genes, resulting in
rhythms in biochemistry, physiology and behavior. Disruption of circadian clocks through genetics or
environmental perturbations such as jet lag or shift-work, can have profound negative consequences
and has been linked to obesity, diabetes, cancer, cardiovascular disease and mental illness. In
particular, circadian clocks exert control over nearly every major metabolic pathway, allowing optimal
utilization of typically cyclic availability of nutrients. Our work is focused generally on
understanding the detailed molecular mechanisms of the mammalian circadian clock
machinery and the mechanisms by which these clocks control rhythmic metabolism.
According to the current model, the core part of this clock mechanism is a negative feedback loop
whereby the transcription factor heterodimer CLOCK/BMAL1 drives transcription of the “clock”
proteins PERIOD (PER) 1, PER 2, CRYPTOCHROME (CRY) 1 and CRY 2 which interact with each
other to repress the activity of CLOCK/BMAL1, and thus their own synthesis. This same
transcriptional mechanism also drives rhythmic expression of many so called “clock-controlled genes”
that ultimately result in the many output rhythms in tissues throughout the body. One of these clock-
controlled genes is Nocturnin, a focus of my laboratory. We have shown that loss of this gene in mice
causes resistance to diet-induced obesity, alters rhythms in cholesterol and triglyceride metabolism
and increases resistance to inflammatory challenges such as LPS. Although the Nocturnin protein is
a member of a family of RNases (the CCR4 deadenylases), we have recently demonstrated that
Nocturnin’s substrate is not RNA, but rather NADP(H). Nocturnin is an NADP(H) phosphatase,
converting NADP(H) to NAD(H). In this proposal we seek to use new mouse models that we have
developed to understand the tissue-specific role of Nocturnin and to disentangle the roles of the two
isoforms (one mitochondrial, the other primarily bound to intracellular membranes). We will also carry
out metabolomic and metabolic flux experiments to determine the effects of circadian regulation of
NADP(H) and NAD(H) levels. In addition, we will validate small molecule modulators of Nocturnin
that we have identified in a high throughput screen and will use these molecules to perturb Nocturnin
activity in cells and mice. Our work on the central mechanism of the core clock will also continue in
the proposed funding period. We have solved crystal structures for the CLOCK/BMAL1 and
CRY2/PER2 complexes and these data have allowed the identification of evolutionarily conserved
functional domains throughout the proteins and revealed additional insights into the mechanisms by
which these proteins operate and set the circadian period. Over the next five years, we will expand
on this information to determine the atomic details of how this clock keeps time.

## Key facts

- **NIH application ID:** 10896929
- **Project number:** 5R35GM127122-07
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Carla B. Green
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $644,919
- **Award type:** 5
- **Project period:** 2018-08-07 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896929

## Citation

> US National Institutes of Health, RePORTER application 10896929, Molecular mechanisms of mammalian circadian clock function - Renewal - 1 (5R35GM127122-07). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10896929. Licensed CC0.

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