# Investigating Circadian Post-Transcriptional Regulation.

> **NIH NIH R35** · RENSSELAER POLYTECHNIC INSTITUTE · 2024 · $423,398

## Abstract

Project Summary/Abstract:
 Circadian rhythms are highly conserved, 24-hour, oscillations that tune human physiology to the
day/night cycle, enhancing fitness by ensuring that appropriate activities occur at biologically advantageous
times. Disruption of proper circadian timing negatively impacts the human long-term medical outlook, making
understanding the mechanism underlying circadian regulation over cellular physiology critical to human health.
Circadian rhythms are controlled via a transcription-translation based negative feedback loop, or clock. The
current paradigm for circadian regulation over physiology, termed the clocks “output”, is that transcriptional
programing generated by the clock drives temporally-specific waves of gene expression. However, our research
has revealed that transcriptional programing cannot wholly account for clock output, as we discovered weak
correlation between mRNAs and proteins that oscillate with a circadian periodicity, particularly in the circadian
regulation of immunometabolism. The mechanisms that control this post-transcriptional regulation are
unknown, but we have shown that intrinsic protein disorder in the repressive complex of the clock may control
the formation of macromolecular complexes to time clock output post-transcriptionally.
 Our immediate research goal is to identify specific pathways by which the clock imparts post-
transcriptional control over the immune response at the biophysical, molecular, and physiological levels. We
hypothesize that circadian post-transcriptional metabolic regulation can tune immune-tissue and sex-specific
rhythms via the formation of time-of-day defined macromolecular protein complexes that are centered around
the repressive complex of the circadian clock. To test this hypothesis, we will create a Conformational/Temporal
Interactome (CiTI) map of circadian repressive complex proteins. We will also investigate the contribution of
sex-specific metabolic post-transcriptional regulation to immune cell functions to demonstrate the effects of
metabolic oscillations on the basal immune response. As a mechanism for keeping time, circadian feedback loops
are highly conserved and much of what is understood about the molecular clock comes from the investigation
of clock model systems. We will therefore exploit the simplicity and reproducibility of fungal and mammalian
model systems to cost-effectively address our hypotheses. Due to the conservation of clock architecture, our
findings will have the potential to define several novel and unrecognized paradigms in clock regulation over
cellular physiology, including the sources and effects of circadian post-transcriptional regulation. These newly
defined paradigms will further our long-term goal of elucidating the fundamental principles of circadian timing
by identifying the mechanistic underpinnings of circadian control over cellular physiology.

## Key facts

- **NIH application ID:** 10901841
- **Project number:** 5R35GM128687-07
- **Recipient organization:** RENSSELAER POLYTECHNIC INSTITUTE
- **Principal Investigator:** Jennifer Marie Hurley
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $423,398
- **Award type:** 5
- **Project period:** 2018-08-15 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901841

## Citation

> US National Institutes of Health, RePORTER application 10901841, Investigating Circadian Post-Transcriptional Regulation. (5R35GM128687-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10901841. Licensed CC0.

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