Monday, March 23, 2026 3/23/2026

Pathogenesis of Airway Stem Cell Abnormalities in Obliterative Bronchiolitis

Award Number: R01HL136370
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Pathogenesis of Airway Stem Cell Abnormalities in Obliterative Bronchiolitis - Project Summary Lung transplantation has become the standard of care for end-stage lung diseases with no available medical therapy. However, long-term survival after lung transplantation is affected by development of chronic lung allograft dysfunction (CLAD), which is progressively fatal and for which there is no effective therapy. Almost 50% of recipients die within five years due to the development of obliterative bronchiolitis (OB) in the allograft, an obstructive type of CLAD. We developed a novel orthotopic lung transplant model in the ferret that closely models human CLAD. Utilizing this model, we showed for the first time that airway submucosal glands (SMGs), a facultative airway stem cell niche, and basal stem cells (BSCs) are depleted in human and ferret OB allografts. We also showed that in human and ferret OB allografts, there is a predominance of Keratin 14 (Krt14) positive BSCs and a loss of Keratin 15 (Krt15) BSCs. This loss of Krt15 in BSCs decreases their proliferative capacity. Additionally, with our collaborator (Dr. Wa Xian), we demonstrated a dominance of pro-fibrotic and pro- inflammatory BSC clones in end-stage lung diseases like chronic obstructive pulmonary disorder, idiopathic pulmonary fibrosis, and cystic fibrosis. We and other investigators have shown that glandular myoepithelial cells (MECs) are a facultative stem cell niche that repairs airway injury and contributes to surface airway BSC and differentiated epithelial cells. The role of these glandular MECs in the transplanted lung remains unclear. Since the bronchial SMG SC niche is not conserved in widely used rodent models, there has been a critical gap in our ability to study and understand how alterations in the bronchial SMG SC niche contribute to impaired epithelial regeneration in the allograft and lead to CLAD. To address, we generated novel ACTA2-CreERT2:ROSA-TG ferrets to lineage label MECs. The overall objective of this proposal is to understand mechanisms leading to CLAD pathogenesis, identify BSC signatures for early detection of CLAD, and identify potential therapeutic targets promoting CLAD. We hypothesize that tight regulation of region-specific airway surface epithelium and SMGs is disrupted in transplanted lungs, which promotes suboptimal regeneration resulting in the expansion of abnormal surface BSCs, the depletion of stem cells in the SMGs, and thus the exacerbation of inflammatory responses that drive CLAD. We will achieve these objectives by addressing the following specific aims: 1) Determine the multipotency of glandular MECs to regenerate surface BSC with abnormal stem cell properties in CLAD. 2) Identify how Keratin 14/15 interact with Stratifin (Sfn) to modulate p63 levels and direct BSC fates. 3) Determine the effect of persistent Krt14 expression coupled with the loss of Krt15 and the emergence of inflammatory basal cell clones on the development of OB in human allografts. The expected outcomes will provide an understanding of the mechanisms leading to the development of CLAD, and identify novel ways to detect, prevent/treat CLAD.


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 = $616,024 )
2026	2026	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Lung Diseases Research	001	7	3/13/2026	NON-COMPETING CONTINUATION	$18,856
2026	2026	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Lung Diseases Research	000	7	3/9/2026	NON-COMPETING CONTINUATION	$597,168
														Subtotal = $616,024

Issue Date FY: 2025 ( Subtotal = $683,512 )
2025	2025	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Lung Diseases Research	000	6	4/8/2025	COMPETING CONTINUATION	$683,512
2025	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Lung Diseases Research	001	5	6/25/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $683,512

Issue Date FY: 2023 ( Subtotal = $589,618 )
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Lung Diseases Research	000	5	3/24/2023	NON-COMPETING CONTINUATION	$589,618
														Subtotal = $589,618

Issue Date FY: 2022 ( Subtotal = $589,618 )
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Lung Diseases Research	001	4	6/14/2022	NON-COMPETING CONTINUATION	$58,963
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Lung Diseases Research	000	4	3/7/2022	NON-COMPETING CONTINUATION	$530,655
														Subtotal = $589,618

Issue Date FY: 2021 ( Subtotal = $589,618 )
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Lung Diseases Research	000	3	3/13/2021	NON-COMPETING CONTINUATION	$589,618
														Subtotal = $589,618

Issue Date FY: 2020 ( Subtotal = $589,618 )
2020	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Lung Diseases Research	000	2	3/23/2020	NON-COMPETING CONTINUATION	$589,618
														Subtotal = $589,618

Issue Date FY: 2019 ( Subtotal = $587,711 )
2019	2019	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	000	1	3/26/2019	NEW	$587,711
														Subtotal = $587,711

Grand Total All Awards = $4,245,719

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Pathogenesis of Airway Stem Cell Abnormalities in Obliterative Bronchiolitis

Award Number: R01HL136370

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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