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Regulation of type II cells in the repair of alveolar epithelial injury

Award Number: R01HL105947
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2012
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Regulation of type II cells in the repair of alveolar epithelial injury - ABSTRACT The maintenance of an intact alveolar epithelial barrier is crucial for lung function. Failure of steady-state replacement or post-injury regeneration of alveolar epithelial cells underlies the pathogenesis of many lung diseases. In recent years, certain subgroups of cells have been identified as putative stem/progenitor cells in the alveolar epithelium during homeostasis and regeneration. However, the identities of these cells and the mechanisms regulating their behavior are still incompletely understood. Recent studies have indicated that some immunity related signaling molecules can regulate the activity of alveolar epithelial progenitors, but the mechanisms that direct these signaling events during lung homeostasis or regeneration have not been well characterized. The objective of this proposal is to determine the distinct roles of immunity related signaling pathways in the regulation of alveoli progenitor cell functions, both during steady-state maintenance as well as post injury repair. An additional goal is to explore the possibility that dysregulation of these signaling processes is related to chronical lung diseases such as emphysema or fibrosis. Two types of epithelial cells cover the lung alveoli: alveolar type I cells (AT1) cover >95% of the surface area and facilitate O2-CO2 exchange, whereas alveolar type II cells (AT2) are responsible for the secretion of surfactant. Importantly, AT2s also function as stem/progenitor cells by undergoing self-renewal and differentiation into AT1s. In preliminary studies, we demonstrated that 1) A small subset of AT2s (1-3% of total) showed stem cell characteristics indicating a role of these cells for steady-state maintenance of alveoli. These cells had intrinsic NFκB and STAT1 activity and these immunity related signals were able to regulate their progenitor functions; 2) After bacterial induced lung injury, more AT2s are activated and behave as facultative stem cells to repair the alveoli. The reparative functions of these cells are regulated by STAT1 and STAT3 mediated signals; and 3) AT2 specific disruption of STAT1 causes sustained fibrosis after bleomycin induced lung injury. This effect is likely induced by an aberrant subpopulation of AT2/AT1 intermediate cells resulting from a failed transition of AT2s to AT1s. Based on these data, we hypothesize that the progenitor function of a subset of AT2s in alveolar homeostasis and post injury regeneration is regulated by distinct immunity related signals. Disruption of these signals is related to the pathogenesis of chronic lung diseases. We will test these ideas with the following specific aims: Aim 1: To determine how NFκB and STAT1 mediated immunity related signaling regulates the stem cell properties of CD44high AT2 subsets during steady-state homeostasis. Aim 2: To determine the role of STAT1/STAT3 dependent, likely NFκB independent, immunity signaling in regulating the facultative progenitor cell functions of AT2 cells in post injury repair. The goal of these studies is to advance our understanding of molecular mechanisms underlying alveolar homeostasis and repair in mouse and human lungs, and to identify novel therapeutic targets to prevent complications related to insufficient epithelial steady-state replacement or repair.


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 = $641,027 )
2026	2026	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	12	8/10/2026	NON-COMPETING CONTINUATION	$641,027
														Subtotal = $641,027

Issue Date FY: 2025 ( Subtotal = $654,109 )
2025	2025	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	001	11	8/22/2025	NON-COMPETING CONTINUATION	$654,109
2025	2020	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	8	1/31/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $654,109

Issue Date FY: 2024 ( Subtotal = $641,027 )
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	10	8/8/2024	NON-COMPETING CONTINUATION	$641,027
														Subtotal = $641,027

Issue Date FY: 2023 ( Subtotal = $654,109 )
2023	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	9	7/21/2023	COMPETING CONTINUATION	$654,109
														Subtotal = $654,109

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	8	7/22/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $399,750 )
2020	2020	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	8	6/12/2020	NON-COMPETING CONTINUATION	$399,750
														Subtotal = $399,750

Issue Date FY: 2019 ( Subtotal = $399,750 )
2019	2019	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	7	6/7/2019	NON-COMPETING CONTINUATION	$399,750
														Subtotal = $399,750

Issue Date FY: 2018 ( Subtotal = $399,750 )
2018	2018	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	6	4/13/2018	COMPETING CONTINUATION	$399,750
2018	2016	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	001	5	8/29/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $399,750

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2016	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	001	5	10/31/2016	EXTENSION WITH OR WITHOUT FUNDS	$117,700
2017	2015	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	4	10/31/2016	NON-COMPETING CONTINUATION	-$117,700
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $398,750 )
2016	2016	UNIVERSITY OF ILLINOIS AT CHICAGO	890 SOUTH MARSHFIELD AVENUE	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	5	3/24/2016	EXTENSION WITH OR WITHOUT FUNDS	$398,750
														Subtotal = $398,750

Issue Date FY: 2015 ( Subtotal = $392,768 )
2015	2015	UNIVERSITY OF ILLINOIS AT CHICAGO	890 SOUTH MARSHFIELD AVENUE	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	4	3/31/2015	NON-COMPETING CONTINUATION	$392,768
														Subtotal = $392,768

Issue Date FY: 2014 ( Subtotal = $390,775 )
2014	2014	UNIVERSITY OF ILLINOIS AT CHICAGO	890 SOUTH MARSHFIELD AVENUE	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	3	4/2/2014	NON-COMPETING CONTINUATION	$390,775
														Subtotal = $390,775

Issue Date FY: 2013 ( Subtotal = $379,610 )
2013	2013	UNIVERSITY OF ILLINOIS AT CHICAGO	890 SOUTH MARSHFIELD AVENUE	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	2	5/13/2013	NON-COMPETING CONTINUATION	$379,610
														Subtotal = $379,610

Issue Date FY: 2012 ( Subtotal = $398,542 )
2012	2012	UNIVERSITY OF ILLINOIS AT CHICAGO	890 SOUTH MARSHFIELD AVENUE	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	1	4/20/2012	NEW	$398,542
														Subtotal = $398,542

Grand Total All Awards = $5,749,967

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Regulation of type II cells in the repair of alveolar epithelial injury

Award Number: R01HL105947

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2012

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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