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Telomere Dysfunction as a cause of Chronic Lung Allograft Dysfunction

Award Number: R01HL151552
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Telomere Dysfunction as a cause of Chronic Lung Allograft Dysfunction - Project Summary Lung transplantation is a potentially lifesaving option for patients with end-stage lung diseases, such as idiopathic pulmonary fibrosis (IPF). However, the median survival following lung transplantation is less than six years, limited primarily by chronic lung allograft dysfunction (CLAD). Emerging data suggest that dysfunction of telomeres, the nucleoprotein caps that protect chromosomes during cellular replication, can result in IPF. It is unknown whether telomere dysfunction also plays a role in CLAD. Were that to be the case, the same pathophysiology that necessitated transplant might also underlie its failure. Our preliminary data show that shorter telomeres in peripheral blood of lung allograft donors predict decreased survival in lung allograft recipients. We also have found that telomere dysfunction in airway progenitor cells is sufficient to induce the pathologic hallmarks of CLAD in an experimental murine model. In humans, progenitor cells such as type II alveolar epithelial cells (AEC2) can proliferate and differentiate to restore epithelial integrity following injury. Thus, AEC2 failure, driven by telomere dysfunction, could lead to denuded alveolar epithelium that is replaced by fibrotic tissue. With the support of this award, we will test the innovative hypothesis that telomere dysfunction is a molecular driver of CLAD. In Study Aim 1, we will evaluate the associations between telomere genetic variants and CLAD in a large, established, multi-center cohort of lung transplant recipients. Common genetic variants resulting in short telomeres will be sequenced, and telomere length will be determined by quantitative PCR. We will use adjusted Cox proportional hazards models to evaluate the links between donor telomere length or genotype and CLAD-free survival time. These findings will help distinguish the contributions of innate and acquired telomere dysfunction to poor post-transplant outcomes. Study Aim 2 will test the association between short allograft AEC2 telomeres and CLAD-free survival in a longitudinal cohort. AEC2 telomere length will be determined by fluorescence-in situ hybridization with a telomere-specific probe (Telo- FISH) on transbronchial biopsy tissues co-labeled with the AEC2 maker, surfactant protein C. We will test the association between AEC2 telomere length within the first 60 days post-transplant and CLAD-free survival using adjusted Cox models. This aim will directly assess the link between early AEC2 telomere dysfunction and CLAD. In Study Aim 3, we will determine whether transplant-associated lung injury and lymphocytic inflammation are associated with time to CLAD, using a novel murine model of telomere-mediated CLAD pathology. Overall, this proposed investigation has the potential to challenge our conceptual understanding of CLAD and inform cutting edge therapeutic interventions. Establishing telomere dysfunction as a molecular driver of CLAD would be new paradigm, potentially transforming clinical approaches and thus improving outcomes for patients with end-stage lung disease.


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 = $0 )
2025	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	002	5	4/21/2025	NON-COMPETING CONTINUATION	$0
2025	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	5	12/19/2024	SUPPLEMENT FOR EXPANSION	$0
2025	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	001	5	4/8/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $329,826 )
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	5	5/13/2024	NON-COMPETING CONTINUATION	$295,653
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	001	5	6/13/2024	SUPPLEMENT FOR EXPANSION	$34,173
														Subtotal = $329,826

Issue Date FY: 2023 ( Subtotal = $389,472 )
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	4	6/16/2023	NON-COMPETING CONTINUATION	$296,642
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	001	4	8/24/2023	SUPPLEMENT FOR EXPANSION	$92,830
														Subtotal = $389,472

Issue Date FY: 2022 ( Subtotal = $299,551 )
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	001	3	6/14/2022	NON-COMPETING CONTINUATION	$29,957
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	3	4/13/2022	NON-COMPETING CONTINUATION	$269,594
														Subtotal = $299,551

Issue Date FY: 2021 ( Subtotal = $295,422 )
2021	2021	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	4/26/2021	NON-COMPETING CONTINUATION	$295,422
														Subtotal = $295,422

Issue Date FY: 2020 ( Subtotal = $297,846 )
2020	2020	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	5/8/2020	NEW	$297,846
														Subtotal = $297,846

Grand Total All Awards = $1,612,117

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Telomere Dysfunction as a cause of Chronic Lung Allograft Dysfunction

Award Number: R01HL151552

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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