# Altered Circadian Rhythm Regulation in Cystic Fibrosis

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $613,685

## Abstract

Although in cystic fibrosis (CF) patients, respiratory and digestive disease is the primary
source of morbidity and mortality there are many other clinically relevant symptoms such as
depression and anxiety, and poor sleep quality, including sleep disturbances, and altered sleep
patterns. Sleep disturbances experienced by individuals with CF are consistent with circadian
rhythm (CR) phase delays. The clinical relevance of CR and sleep regulation in CF can be seen
in studies that demonstrate CF patients with poor sleep quality have more severe lung disease
and poorer outcomes over time. Whether CR disruption in CF is a direct effect of impaired CFTR
function or a secondary manifestation of disease progression is currently unclear. Also unclear is
the efficacy of modulatory therapy in CF in reversing these phenotypes. We have recently
published that CR gene expression is altered in a CF mouse model suggesting that CR
dysregulation is a primary manifestation of CF. Mechanistically, we have previously reported
alterations in microtubule regulation in CF cells. These findings lead to the hypothesis that CR
regulation in CF is altered due microtubule instability and consequent reductions in melatonin
production. Microtubules have been suggested to play an important role in CR, and we have
previously demonstrated that CF cells display reduced acetylation and slower microtubule
formation rates. We have also recently published that depletion of a microtubule modulating
protein (tubulin polymerization promoting protein, TPPP) from mice replicates CF-like CR
disruptions that support a role of microtubules in CF phenotypes. Preliminary data demonstrate
that CF mice produce reduced levels of melatonin, a key CR regulator and known regulator of
microtubule stability. These data suggest melatonin and/or microtubule targeted compounds as
possible therapeutic interventions that can augment modulator therapy or allow an alternative
approach to address CR-related phenotypes in CF patients. The goals of the study are to
determine the role of CFTR in CR regulation and if CFTR correction influences CR gene
expression and related behavioral outcomes. We also will strive to understand the cellular
mechanisms involved in these regulatory relationships that can be therapeutically targeted. To
achieve these goals, the following specific aims will be studied: Aim 1. To determine the CFTR-
dependency of CR regulation and the efficacy of highly-effective CFTR modulators in reversing
CF-related CR phenotypes. Aim 2. To identify mechanisms of CR dysregulation in CF. Aim 3.
To determine the effect of CFTR modulators on circadian rhythm and to determine melatonin
production in children and adolescents with CF.

## Key facts

- **NIH application ID:** 10797014
- **Project number:** 5R01HL156928-03
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Rebecca J Darrah
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $613,685
- **Award type:** 5
- **Project period:** 2022-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10797014

## Citation

> US National Institutes of Health, RePORTER application 10797014, Altered Circadian Rhythm Regulation in Cystic Fibrosis (5R01HL156928-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10797014. Licensed CC0.

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