# Circadian regulation of physiological functions

> **NIH NIH R35** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $14,835

## Abstract

SUMMARY: My lab studies circadian-regulated processes and their contributions to health and disease.
Circadian regulation refers to daily oscillations in biological functions and is an evolutionarily conserved feature
from bacteria to humans. At its core, circadian regulation is governed by a transcriptional negative feedback
loop called the circadian clock. Circadian clocks generate 24-hour oscillations in the expression of hundreds of
genes in almost every tissue examined and drive the daily oscillation of cellular, tissue-specific, and behavioral
functions. Chronic disruption of circadian regulation due to jetlag or night-shift work is associated with multiple
defects in innate immunity, metabolism, and sleep. Many disease states are also associated with loss of
circadian regulation, including bacterial infection, metabolic diseases, and neurological diseases. Despite the
known profound effects of loss of circadian regulation on human physiology, a major gap in knowledge is the
identification of circadian-regulated functions that contribute to the pathogenesis of specific diseases.
 In the last funding period, our MIRA supported the development of tools to enhance or inhibit Drosophila
circadian clocks; the investigation of glial function in both Drosophila and mice; and the investigation of a core
function for sleep in Drosophila. In the current proposal, we focus on circadian-regulated metabolism, which has
emerged as a major theme in our work. We describe two projects involving circadian-regulated metabolism in
Drosophila: sensitivity to oxidative stress due to chronic short sleep (Project 1) and metabolic regulation of host
tolerance of bacterial infection (Project 2).
· Project 1: One of the most obvious manifestations of circadian rhythm is sleep. Sleep, or obligate rest
 during the 24-hour circadian cycle, is evolutionarily conserved. Yet the physiological function of sleep
 remains unclear. Our published MIRA-funded results support the hypothesis that a key function of sleep is
 defense against oxidative stress. Our more recent preliminary data suggest that chronic short sleep causes
sensitivity to oxidative stress due to underlying changes in metabolism. We will investigate this in Project 1.
· Project 2: There are two types of defense mechanisms against infection: resistance and tolerance.
Resistance mechanisms kill pathogens, while tolerance mechanisms limit the pathogenic effects of infection.
Tolerance is much less well understood than resistance. In NIGMS-funded research, my lab previously
identified a circadian-regulated, TORC2-mediated mechanism of host tolerance against B. cepacia infection.
In preliminary data, we found that Sting mutants also have increased tolerance against B. cepacia infection.
The Stimulator of Interferon Genes (STING) pathway is a conserved innate immune response and known
resistance mechanism. STING also has a second distinct function in both mammals and Drosophila:
regulation of lipid metabolism. We wi...

## Key facts

- **NIH application ID:** 11091111
- **Project number:** 3R35GM127049-07S1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Michele M Shirasu-Hiza
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $14,835
- **Award type:** 3
- **Project period:** 2018-05-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11091111

## Citation

> US National Institutes of Health, RePORTER application 11091111, Circadian regulation of physiological functions (3R35GM127049-07S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11091111. Licensed CC0.

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