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Circadian Signatures in Chronic Lung Disease

Award Number: R01HL152968
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Circadian Signatures in Chronic Lung Disease - PROJECT SUMMARY/ABSTRACT Circadian rhythms are an important yet poorly understood feature of chronic lower respiratory disease. In airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), nocturnal exacerbations are a disease-defining characteristic in which normal circadian swings in airway resistance are pathologically amplified. Circadian rhythms are generated by a cell-autonomous molecular clock that orchestrates tissue- specific rhythms in gene expression, leading to oscillations in physiology including in the lung. Research suggests that molecular clock function specifically within airway epithelial cells regulates innate antimicrobial responses. Such responses are critical in chronic lung disease because they may determine whether an encounter with a virus or other pathogen triggers a clinical exacerbation. Currently, there is no information on the circadian regulatory program within the human lung and how chronic disease might rewrite this regulation to drive pathogenesis. Here we show that chronic lung disease alters rhythms in circadian clock gene expression in human bronchial epithelial cells (HBECs) from patients. We demonstrate that HBECs express circadian transcriptomes encompassing hundreds of genes and exhibit disease-specific patterns that can be further altered by acute viral infection. As such, we hypothesize that chronic airway disease reprograms circadian gene expression in airway cells thereby influencing virus susceptibility. The overarching goal of this project is to translate circadian biology into disease-modifying treatments for patients with chronic airway disease by mitigating or preventing virally triggered clinical exacerbations. Aim 1: Identify disease-specific circadian gene expression programs regulating antiviral responses in asthma and COPD patients. Using a unique repository of HBECs developed by our group that were isolated from human lung explants, we will determine the circadian transcriptomes of HBECs obtained from asthma and COPD patients and compare these to donors without chronic airway disease. In parallel, we will phenotype HBECs in terms of their susceptibility to acute influenza A virus (IAV) infection in the presence or absence of circadian clock disruption. Observations in HBECs will be backed by single cell imaging of circadian rhythms and a first-of-its-kind analysis of in vivo human airway circadian gene expression using serial airway brushing samples obtained from organ transplant donors after brain death while they await organ procurement. Aim 2: Discover evolutionarily conserved circadian reprogramming in chronic airway disease. We will use a well characterized mouse model of asthma/COPD- like airway remodeling with known clock regulation of antiviral responses. Using this model, we will examine lung circadian reprogramming of gene expression and leukocyte trafficking by chronic airway disease and determine the dependency of this program on the airway epithelial cell peripheral clock. These studies will be backed by in vivo imaging of airway clock gene expression in mice using bioluminescent reporters.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = -$2,352 )
2026	2023	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	National Center on Sleep Disorders Research	000	4	12/4/2025	NON-COMPETING CONTINUATION	-$2,352
														Subtotal = -$2,352

Issue Date FY: 2023 ( Subtotal = $603,572 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	National Center on Sleep Disorders Research	000	4	5/17/2023	NON-COMPETING CONTINUATION	$603,572
														Subtotal = $603,572

Issue Date FY: 2022 ( Subtotal = $610,245 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	National Center on Sleep Disorders Research	000	3	7/13/2022	NON-COMPETING CONTINUATION	$610,245
														Subtotal = $610,245

Issue Date FY: 2021 ( Subtotal = $619,980 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	National Center on Sleep Disorders Research	000	2	5/25/2021	NON-COMPETING CONTINUATION	$619,980
														Subtotal = $619,980

Issue Date FY: 2020 ( Subtotal = $619,653 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	National Center on Sleep Disorders Research	000	1	7/22/2020	NEW	$619,653
														Subtotal = $619,653

Grand Total All Awards = $2,451,098

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Circadian Signatures in Chronic Lung Disease

Award Number: R01HL152968

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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