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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: 07/31/2025

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Airway epithelial cell and lymphocyte interactions in chronic lung allograft dysfunction pathogenesis - Project Summary/Abstract 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 is developing. We have published gene expression changes associated with CLAD validated across our centers. This proposal will leverage this innovative approach to understand the mechanisms of CLAD pathogenesis. Our preliminary data show an early upregulation of hypoxia pathways in airway brushings including genes that recruit and activate cytotoxic 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. We also observed upregulation of tumor necrosis factor superfamily (TNFSF) co-stimulatory molecules that may drive alloimmune responses. Finally, our data show apoptosis in airway club cells, the protectors and progenitors of small airways, in association with TNF-related apoptosis-inducing ligand (TRAIL). Single cell investigations in airways 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 leads to TNFSF-mediated T cell activation and subsequent apoptosis of airway club cells 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 determine the airway-specific gene signature of hypoxia and test whether this precedes CLAD. 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. Then in Aim 3, we will examine 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 with rigor. The gene expression signatures defined by cell type and time course of CLAD that will be developed 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 = $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	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	000	3	12/4/2024	SUPPLEMENT FOR EXPANSION	$71,515
														Subtotal = $71,515

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 = $1,933,195

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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: 07/31/2025

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