# The role of circadian clock proteins in innate and adaptive immunity

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $360,832

## Abstract

ABSTRACT
 Within each mammalian cell is a core set of circadian clock proteins that regulate the cellular biology
supporting more complex organ physiologies. The central nervous system, entrained by the principle
environmental cue – light, synchronizes these peripheral cellular ‘clocks’ across the entire organism, which
enables the host organism to anticipate and prepare for the stresses of the active day (e.g., metabolic
demands, septic threat). The current evidence, including data derived from our own research program,
highlight the profound influence individual clock proteins have on the physiologic capacity with which an
organism responds to stress. We first identified that the spectrum of light is a critical determinant of its effects
on mammalian biology, and that the short wavelength visible blue spectrum favorably modifies the
biology and outcome of sepsis. In murine models of intraabdominal sepsis and Klebsiella pneumoniae (KP)
pneumonia, exposure to blue light after sepsis enhanced immune competence, as evidenced by more efficient
clearance of bacteria from the septic focus, reduced bacterial dissemination, and attenuated systemic
inflammation. The mechanism involved an optic-cholinergic pathway that induced the clock protein Rev-Erba
in immune tissues of the spleen and Mj. A Rev-Erba agonist similarly enhance immune function in both in vitro
and in vivo studies. Our overarching hypothesis is that the cellular state of the clock protein Rev-Erba is
a critical determinant of immune competence and can be modulated to improve the outcome of sepsis.
We specifically hypothesize that Rev-Erba regulates the protein machinery supporting the immune
phenotype of the mononuclear phagocyte and B cell and is vital to an efficient immune response to
microbial threat.
 In Aim 1 we will study the physiologic and cellular mechanisms by which blue light and the clock protein
Rev-Erba regulate monocyte recruitment to the spleen and peripheral tissues and differentiation into a type of
monocyte highly efficient in bacterial clearance, using a model of KP pneumonia. In Aim 2, we will explore the
mechanisms by which blue light and Rev-Erba modulate B cell PI3K-AKT-mTOR signaling and actin assembly
to mediate B cell differentiation, activation, MHC II antigen presentation, and antibody production. As these
mechanisms are metabolically demanding and ATP-dependent, we will (Aim 3) determine the mechanisms by
which Rev-Erba modulates mitochondrial dynamics to support oxidative metabolism and thereby the
phenotype of immune cells during sepsis.
 The ramifications of light on health and disease remain to be convincingly defined. This proposal will define
the biological mechanisms through which circadian clock proteins beneficially alter the host response to acute
infectious insult. We will define the dimensions of light and state of clock proteins that are optimally protective
and examine their biological relevance and potential therapeutic value in studies of pat...

## Key facts

- **NIH application ID:** 10708936
- **Project number:** 5R01GM145674-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** MATTHEW Randall ROSENGART
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $360,832
- **Award type:** 5
- **Project period:** 2022-09-26 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10708936

## Citation

> US National Institutes of Health, RePORTER application 10708936, The role of circadian clock proteins in innate and adaptive immunity (5R01GM145674-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10708936. Licensed CC0.

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