# Investigating Circadian Mechanisms of Cellular Resilience: Rhythmic Condensates, Disorder, and Stress

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2022 · $420,518

## Abstract

PROJECT SUMMARY (ABSTRACT)
The endogenous circadian clock that synchronizes cellular physiology with the earth's light/dark cycle affects
all aspects of physiology – from molecular to cellular to behavioral. The circadian system has an integral role in
promoting cellular resilience in the face of environmental or internal perturbation. Circadian disruption has been
linked with cardiovascular disease, obesity, pulmonary disease, and neuropsychiatric disorders, highlighting
the importance of fundamental knowledge of cellular clock mechanisms for clinical medicine. While the
molecular basis for circadian timekeeping has been exquisitely defined, how the clock responds to the
environment to maintain cellular homeostasis remains mostly unknown.
 We will test the hypothesis that the core circadian clock protein CLOCK is a stress sensor that
transmits environmental information through structural elements in its intrinsically disordered region to both the
circadian timekeeping mechanism and the stress-response machinery. We have discovered that the RNA
chaperone DDX3X critically regulates the sensitivity of CLOCK to environmental stimuli such as temperature
and has potent effects on both circadian timekeeping and cellular resilience. We will determine how CLOCK
mechanistically integrates with the cellular stress machinery, including the heat shock response. Beyond its
role as a stress sensor, we will investigate how the circadian system and CLOCK adaptively organize the
biochemical state of the proteome, sculpting the circadian assembly of biological pathways involved in
homeostasis. We will test these cellular data in animals by measuring how genetic and behavioral models of
circadian disruption and sleep deprivation re-program the rhythmicity of protein assemblies. Finally, we will
apply these discoveries to human peripheral blood samples in which we have, for the first time, identified
rhythms of protein synthesis. This proposal is strengthened by its multi-scaled and interdisciplinary approaches
that harness the expertise of the PI in chronobiology, cell biology, and biochemistry in collaboration with
experts in human circadian biology (Klerman), proteomics and phosphoproteomics (Asara), live cell and
super-resolution imaging (Chen), and imaging and assay development (Barrett).
 Our hypothesis is that the molecular mechanisms for circadian resilience and their failure during stress
underlie a maladaptive feedback loop that connects integrated cellular stress responses with circadian
misalignment. Determining the mechanisms by which the circadian clock supervises, senses, and responds to
environmental stimuli is a crucial challenge for linking circadian disruption to disease mechanisms. My clinical
background and experience as a pediatric neurologist trained in sleep medicine supports and informs my
research interest in sleep and circadian disorders. We anticipate that the successful testing of this hypothesis
will offer novel and pharmacologically ac...

## Key facts

- **NIH application ID:** 10403440
- **Project number:** 5R01HL151368-03
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Jonathan Oren Lipton
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $420,518
- **Award type:** 5
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10403440

## Citation

> US National Institutes of Health, RePORTER application 10403440, Investigating Circadian Mechanisms of Cellular Resilience: Rhythmic Condensates, Disorder, and Stress (5R01HL151368-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10403440. Licensed CC0.

---

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