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Lung Remodeling Mediated by Telomere Dysfunction in Alveolar Type II Cells

Award Number: R01HL139897
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/05/2018
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Lung Remodeling Mediated by Telomere Dysfunction in Alveolar Type II Cells - Idiopathic pulmonary fibrosis (IPF) is a genetically mediated, progressive, lung disorder. Evidence points to dysfunctional epithelial telomeres as a core disease-initiating abnormality in IPF. There is limited knowledge of the relationship between alveolar type 2 (AT2) cell telomere dysfunction and the cellular and molecular elements of the remodeled fibrotic lung. Attempts to elucidate this connection in mouse models of telomere dysfunction have been limited by the inherently long telomeres of mice and the use additional fibrogenic stimuli such as low dose bleomycin, which may obscure the distinct input of dysfunctional telomeres to the pathobiology. This proposal seeks to overcome these limitations by applying a novel model of progressive lung fibrosis driven solely by telomere dysfunction isolated to AT2 cells (TRF1SC mice) to study mechanisms of lung fibrosis. The hypothesis is that events developing in TRF1SC mice mimic early epithelial-specific events in the pathogenesis of IPF and that this model will provide new insights into the origins of epithelial cell remodeling observed in IPF. To test this hypothesis, the following aims will be explored: Aim 1 proposes to use TRF1SC/p53-/- mice to establish whether p53 is a molecular mediator of progressive epithelial transdifferentiation and remodeling driven by AT2 cell telomere dysfunction in TRF1SC mice. Single cell RNAseq (scRNAseq) will be used to define the role of p53 on reprogramming of TRF1SC AT2 cells after telomere uncapping, and the appearance of other profibrotic epithelial cell subtypes. Aim 2 proposes to study TRF1SC/TZAP-/- mice to test the hypothesis that the latency of onset of fibrosis in TRF1SC mice requires telomere trimming. TRF1SC/TZAP-/- mice will be treated with tamoxifen for 9 months and measures of telomere attrition, epithelial remodeling, and fibrosis compared to control TRF1SC mice. scRNAseq will be used to define the contribution of telomere trimming to AT2 cell reprogramming in control, TRF1SC, and TRF1SC/TZAP-/- mice. Telomere trimming in normal AT2 cells will be investigated by studying changes in telomere lengths in aged TZAP-/- mice. Aim 3 proposes to culture IPF and control AT2 cells in the presence and absence of hTERT overexpression in an organoid system to establish whether augmenting telomere length restores epithelial cell fate and function of IPF lung epithelial cells. Comparative endpoints include: telomere length measures, DNA damage detected by co-staining for γH2AX and TRF2, senescence reprogramming by β-galactosidase and p16 staining. AT2 cell transdifferentiation into AT1 cells and by qPCR and immunostaining. The influence of hTERT overexpression on other IPF epithelial cell subtypes will be studied by comparing gene expression by scRNAseq of mixed populations of IPF epithelial cells cultured in the presence or absence of hTERT. If successful, these studies will provide an understanding into cell-cell interactions, mediated by telomere dysfunction, driving lung fibrosis in IPF.


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 = $719,516 )
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	7	2/26/2025	NON-COMPETING CONTINUATION	$719,516
2025	2021	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	4	2/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $719,516

Issue Date FY: 2024 ( Subtotal = $783,378 )
2024	2024	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	6	1/17/2024	NON-COMPETING CONTINUATION	$719,429
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	6	6/20/2024	NON-COMPETING CONTINUATION	$63,949
														Subtotal = $783,378

Issue Date FY: 2023 ( Subtotal = $799,275 )
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	5	3/28/2023	COMPETING CONTINUATION	$799,275
2023	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	4	3/27/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $799,275

Issue Date FY: 2021 ( Subtotal = $592,668 )
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	4	6/16/2021	NON-COMPETING CONTINUATION	$592,668
														Subtotal = $592,668

Issue Date FY: 2020 ( Subtotal = $592,668 )
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	3	6/22/2020	NON-COMPETING CONTINUATION	$592,668
														Subtotal = $592,668

Issue Date FY: 2019 ( Subtotal = $588,998 )
2019	2019	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	6/7/2019	NON-COMPETING CONTINUATION	$588,998
														Subtotal = $588,998

Issue Date FY: 2018 ( Subtotal = $587,022 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	000	1	7/5/2018	NEW	$587,022
														Subtotal = $587,022

Grand Total All Awards = $4,663,525

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Lung Remodeling Mediated by Telomere Dysfunction in Alveolar Type II Cells

Award Number: R01HL139897

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/05/2018

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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