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Epigenetic mechanisms of inflammatory memory propagation in human airway epithelia

Award Number: R01HL163024
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/05/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Epigenetic mechanisms of inflammatory memory propagation in human airway epithelia - PROJECT SUMMARY / ABSTRACT Asthma and chronic bronchitis are among the top causes of death and hospitalizations worldwide. Chronic airway inflammation in asthma causes goblet cell metaplasia (GCM), mucus hypersecretion, and airway plugging, resulting in respiratory failure and poor quality of life. The mechanism for acquisition and persistence of chronic inflammation is not known. Current anti-inflammatory treatments for asthma can be ineffective and are not curative; chronic GCM resumes upon treatment discontinuation. Therefore, there is an urgent need to understand the mechanisms of chronic inflammation and GCM in asthma. Host genetics and the environment both contribute to asthma; the environment contributes to asthma by inducing immune and airway epithelial epigenetic memory. Basal stem cells in the airway epithelium may acquire epigenetic changes and act as a memory reservoir; as cellular turnover in the lungs occurs, basal cells replenish the epithelium and may propagate inflammatory memory, causing GCM. The importance of airway epithelial epigenetic memory in chronic lung inflammation is an emerging area of research. The central hypothesis of this proposal is that basal stem cells acquire IL-13-induced epigenetic changes and propagate inflammatory memory as they mitotically replenish the epithelium causing GCM and abnormal epithelial function; we plan to address the following aims: Specific Aim 1: Identify mechanisms of IL-13-induced memory in human large and small airway epithelia basal cells using transcriptomic, epigenomic, and clonotype analysis; we will determine the effect of IL-13-induced memory on GCM and function of airway epithelia. Specific Aim 2: Determine epigenetic inflammatory memory in asthmatic nasal airway basal cells obtained non- invasively using nasal brushings and in vitro expansion; this will allow us to determine how memory acquired by basal cells in asthma contribute to GCM, and whether inflammatory memory in asthma is IL-13- driven. Specific Aim 3: Investigate whether epigenetic changes acquired by tracheobronchial airway basal cells in vivo determine response to IL-13 in vitro leveraging a biobank of primary tracheobronchial basal cells developed by the PI; we will determine the epigenetic, transcriptional and phenotypic memory of epithelia highly susceptible to and epithelia resistant to IL-13-induced GCM. We will also determine whether drugs targeting GCM revert epigenetic memory. With the completion of this proposal, we expect to have identified A) novel mechanisms, B) treatment targets, and C) biomarkers and precision medicine strategies in asthmatics and other chronic inflammatory lung diseases. This is a first step to enable curative asthma treatments. We will further the NHLBI’s mission to “translate basic discoveries into clinical practice” and to “enhance the health of all individuals so that they can live longer and more fulfilling lives.”


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 = $550,017 )
2026	2026	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Lung Diseases Research	001	5	3/25/2026	NON-COMPETING CONTINUATION	$16,837
2026	2026	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Lung Diseases Research	000	5	2/13/2026	NON-COMPETING CONTINUATION	$533,180
														Subtotal = $550,017

Issue Date FY: 2025 ( Subtotal = $561,241 )
2025	2025	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Lung Diseases Research	000	4	1/17/2025	NON-COMPETING CONTINUATION	$505,119
2025	2025	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Lung Diseases Research	001	4	8/8/2025	NON-COMPETING CONTINUATION	$56,122
														Subtotal = $561,241

Issue Date FY: 2024 ( Subtotal = $549,375 )
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Lung Diseases Research	001	3	6/14/2024	NON-COMPETING CONTINUATION	$44,847
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Lung Diseases Research	000	3	12/22/2023	NON-COMPETING CONTINUATION	$504,528
														Subtotal = $549,375

Issue Date FY: 2023 ( Subtotal = $560,943 )
2023	2023	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Lung Diseases Research	001	2	1/13/2023	NON-COMPETING CONTINUATION	$504,850
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Lung Diseases Research	002	2	3/3/2023	NON-COMPETING CONTINUATION	$56,093
2023	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Lung Diseases Research	000	1	12/1/2022	NEW	$0
														Subtotal = $560,943

Issue Date FY: 2022 ( Subtotal = $577,695 )
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Lung Diseases Research	000	1	5/2/2022	NEW	$577,695
														Subtotal = $577,695

Grand Total All Awards = $2,799,271

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Epigenetic mechanisms of inflammatory memory propagation in human airway epithelia

Award Number: R01HL163024

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/05/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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