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The Role of Telomeres in Lung Transplant Recipient Immunity and Outcomes

Award Number: R01HL166265
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/05/2023
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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The Role of Telomeres in Lung Transplant Recipient Immunity and Outcomes - Project Summary Lung transplantation (LTx) is the only therapeutic option for patients with end-stage lung disease and idiopathic pulmonary fibrosis (IPF) is the most common indication in North America. However, IPF lung transplant recipients (IPF-LTRs) have worse transplant survival compared to all other lung diseases. Mutations in the genes responsible for telomere maintenance are the most common identifiable cause of IPF and our group recently showed that lung transplantation enriches for patients with telomere-mediated disease with as many as a quarter of patients having an identifiable rare variant. Patients with defects in telomere-maintenance genes have an array of immunologic abnormalities that render them susceptible to viral infections. Despite having a weakened immune system, these patients have been reported to reject donor lungs at similar or faster rates than individuals without telomere-mediated disease. The mechanism responsible for this phenomenon are unknown. Based on our preliminary data, we hypothesize that lung transplantation unmasks a complex syndrome that impacts viral host defense, immunosuppression tolerance and allograft rejection. Further, we hypothesize that impaired adaptive immunity is exacerbated by Cytomegalovirus infection by augmenting immunosenescence, however alloimmune and other immune mechanisms can offset and facilitate lung rejection outcomes in transplant recipients with short telomeres. We have divided our approach into three related and synergistic aims. In Aim 1, we examine the consequences of primary CMV infection in patients with telomere-mediate disease and test if two hits, telomere dysfunction and CMV infection, cooperate to drive immune senescence. In Aim 2, we explore the mechanisms that are responsible for lung rejection in individuals with weakened immune systems. Finally, in Aim 3, we test if our recent findings from the University of Pittsburgh can be replicated and extended in a multi- center group of patients from the Lung Transplant Outcomes Group and examine keep outcomes following lung transplantation when stratified by genetic findings and telomere length. We expect that these studies will help improve care and outcomes in patients with telomere-mediated 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: 2026 ( Subtotal = $695,991 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	001	4	3/13/2026	NON-COMPETING CONTINUATION	$21,306
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	000	4	2/20/2026	NON-COMPETING CONTINUATION	$674,685
														Subtotal = $695,991

Issue Date FY: 2025 ( Subtotal = $707,484 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	000	3	3/25/2025	NON-COMPETING CONTINUATION	$636,735
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	001	3	8/18/2025	NON-COMPETING CONTINUATION	$70,749
														Subtotal = $707,484

Issue Date FY: 2024 ( Subtotal = $697,995 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	001	2	6/20/2024	NON-COMPETING CONTINUATION	$56,980
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	000	2	5/4/2024	NON-COMPETING CONTINUATION	$641,015
														Subtotal = $697,995

Issue Date FY: 2023 ( Subtotal = $723,541 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	000	1	3/5/2023	NEW	$723,541
														Subtotal = $723,541

Grand Total All Awards = $2,825,011

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The Role of Telomeres in Lung Transplant Recipient Immunity and Outcomes

Award Number: R01HL166265

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/05/2023

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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