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Mechanisms of Telomere-Mediated Lung Disease

Award Number: R01HL135062
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/10/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Mechanisms of Telomere-Mediated Lung Disease - Abstract Telomere dysfunction has emerged as a primary contributor to diseases within the human lung. Over the past five years, our group has shown that telomere dysfunction limits the proliferative capacity of lung epithelial cells and renders the lung susceptible to injury. In addition, we have found that the senescent lung epithelium secrets a number of bioactive proteins that have unexpected roles in physiology and lung repair. Here we extend our findings to test the centrality of the type II alveolar epithelial cell (AEC2). We build on previous studies that have investigated the roll of AEC2 in disease pathogenesis and repair of the lung epithelium. Our preliminary data support the selective loss of AEC2 with age in humans and extensive loss in the context of disease. Based on these findings, we generated a novel model of chronic AEC2 insufficiency that recapitulates several aspects of idiopathic pulmonary fibrosis (IPF), including a peripheral predilection, depletion of AEC2, and progressive fibrosis that is eventually lethal. This proposal will extend these findings and explore the hypothesis that chronic AEC2 insufficiency is a unifying pathologic mechanism in IPF. In aim 1, we comprehensively and unambiguously map every AEC2 throughout the mouse lifespan including very old mice and examine the changes in spatial organization of AEC2 with injury using a novel whole organ imaging methodology. In aim 2, we characterize a novel model of progressive fibrosis in the mouse that is driven by AEC2 insufficiency. We will examine functional, cellular, and molecular changes throughout development of fibrosis. Aim 3 will test a novel approach to lengthen telomere based on somatic mutations that are acquired in patients with IPF. Together, these aims will test a novel hypothesis that unifies the pathologic mechanisms of IPF and generates new tools and resources for the pulmonary community.


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 = $747,166 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	000	7	7/12/2025	NON-COMPETING CONTINUATION	$747,166
														Subtotal = $747,166

Issue Date FY: 2024 ( Subtotal = $700,488 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	001	6	9/4/2024	COMPETING CONTINUATION	$735,366
2024	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	000	5	1/26/2024	NON-COMPETING CONTINUATION	-$34,878
														Subtotal = $700,488

Issue Date FY: 2022 ( Subtotal = $384,352 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	000	5	7/1/2022	NON-COMPETING CONTINUATION	$384,352
														Subtotal = $384,352

Issue Date FY: 2021 ( Subtotal = $384,352 )
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	000	4	7/5/2021	NON-COMPETING CONTINUATION	$384,352
														Subtotal = $384,352

Issue Date FY: 2020 ( Subtotal = $384,352 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Lung Diseases Research	000	3	6/30/2020	NON-COMPETING CONTINUATION	$384,352
														Subtotal = $384,352

Issue Date FY: 2019 ( Subtotal = $388,069 )
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Lung Diseases Research	000	2	6/24/2019	NON-COMPETING CONTINUATION	$388,069
														Subtotal = $388,069

Issue Date FY: 2018 ( Subtotal = $373,290 )
2018	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Lung Diseases Research	000	1	7/9/2018	NEW	$373,290
														Subtotal = $373,290

Grand Total All Awards = $3,362,069

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Mechanisms of Telomere-Mediated Lung Disease

Award Number: R01HL135062

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/10/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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