Wednesday, September 17, 2025 9/17/2025

Airway epithelial cell and lymphocyte interactions in chronic lung allograft dysfunction pathogenesis

Award Number: R01HL161048
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Airway epithelial cell and lymphocyte interactions in chronic lung allograft dysfunction pathogenesis - The major barrier to long term survival following lung transplantation is a progressive loss of lung function, termed chronic lung allograft dysfunction (CLAD), for which constrictive fibrosis in small airways is a pathologic hallmark. CLAD affects over half of lung transplant recipients by 4 years post-transplant and negates much of the quality of life and functional improvements associated with transplantation. Pitt, Toronto, and UCSF Lung Transplant programs have refined transcriptional analysis of small airway brushings from lung transplant recipients as a novel technique to understand the gene expression changes at the anatomical site where CLAD pathology develops. We have published gene expression changes associated with CLAD validated across our centers. This proposal leverages this innovative approach to understand mechanisms of CLAD pathogenesis. Our preliminary data show an early upregulation of hypoxia pathways in airway brushings including genes that recruit and activate cytotoxic T lymphocytes using both airway epithelial cell culture in hypoxic conditions and pathway analysis of airway brush transcriptomes. This hypoxia signaling may reflect disordered microvasculature, absent bronchial circulation, and vascular inflammation associated with lung transplant. In recruited T lymphocytes, we also observed upregulation of tumor necrosis factor superfamily (TNFSF) genes, which are major drivers of apoptosis in lymphocyte targets. Our data show preferential apoptosis in airway club cells, the protectors and progenitors of small airways, in association with upregulated TNF-related apoptosis- inducing ligand (TRAIL) expression. Our single cell investigations in airway brushings and bronchoalveolar lavage (BAL) fluid show the segregation of these pathways across epithelial and lymphoid cell types. Based on these data, we hypothesize that airway hypoxia precedes TNFSF gene expression and T cell-mediated airway club cell apoptosis that drive CLAD pathogenesis. To test this hypothesis, we will generate parallel cohorts investigating bulk and single cell transcriptomes of CLAD versus controls across three centers, allowing for rigorous cross-validation of gene expression signatures. We will complement these studies with cell culture- based methods to determine mechanisms driving these gene expression changes. In Aim 1, we will quantify hypoxia-related transcripts in airway brush cells with respect to CLAD and determine how hypoxia can promote lymphocytic inflammation. In Aim 2, we will determine the cellular sources and kinetics of TNFSF co-stimulatory molecule expression in CLAD using airway brushes and BAL fluid. In Aim 3, we will investigate whether TRAIL preferentially induces club cell apoptosis. The synergy of three large lung-transplant translational research programs with world-class cross-institutional biostatistical infrastructures provides a unique opportunity to address this hypothesis rigorously. The cell-specific gene expression signatures over the time course of CLAD development that will be generated through this study are critically needed as surrogate biomarkers to support clinical trials of targeted therapies and to pioneer a novel approach to CLAD diagnosis.


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: 2025 ( Subtotal = $790,874 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	001	3	6/6/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	003	3	8/7/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	002	3	7/14/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	005	4	8/22/2025	SUPPLEMENT FOR EXPANSION	$104,953
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	006	4	8/22/2025	SUPPLEMENT FOR EXPANSION	$153,971
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	000	3	12/4/2024	SUPPLEMENT FOR EXPANSION	$71,515
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	007	4	9/3/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	004	4	8/18/2025	NON-COMPETING CONTINUATION	$460,435
														Subtotal = $790,874

Issue Date FY: 2024 ( Subtotal = $602,118 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	000	3	8/16/2024	NON-COMPETING CONTINUATION	$602,118
														Subtotal = $602,118

Issue Date FY: 2023 ( Subtotal = $614,406 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	2	8/16/2023	NON-COMPETING CONTINUATION	$614,406
														Subtotal = $614,406

Issue Date FY: 2022 ( Subtotal = $645,156 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	1	8/15/2022	NEW	$645,156
														Subtotal = $645,156

Grand Total All Awards = $2,652,554

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Airway epithelial cell and lymphocyte interactions in chronic lung allograft dysfunction pathogenesis

Award Number: R01HL161048

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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