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Defining molecular signals that influence airway basal cell renewal and growth

Award Number: F31HL149381
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2023

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Defining molecular signals that influence airway basal cell renewal and growth - PROJECT SUMMARY Basal cells (BCs) of mammalian airways are resident stem cells of the pseudostratified epithelium of the airways and understanding how they are regulated and maintained will be important for understanding their aberrant growth in disease, such as COPD, cystic fibrosis and cancer, as well as for developing novel methods for harnessing BCs for the purposes of regenerative medicine. The Hippo signaling pathway has emerged as an important regulator of BC growth. Hippo signaling controls the activity of the transcriptional regulators YAP and TAZ (YAP/TAZ) by restricting nuclear YAP/TAZ localization in mature differentiated airway cells. Nuclear YAP activity has been shown to promote BC growth in the airways and has been shown to play important roles in a variety of stem cell populations in other tissues and organs. YAP is implicated in maintaining the airway BC fate through direct association with the basal cell specific transcription factor, p63. Airway basal stem cells play important roles lung injury repair, but the signals that regulate their growth and self-renewal are poorly understood. Our studies, as well as others, indicate that the nuclear activity of the transcriptional regulator YAP plays important roles in airway basal cell growth and in this proposal, we aim to understand the roles and regulation of YAP activity in this context. In this proposal we aim to use genetic mouse models which contain conditional knockouts of Hippo pathway regulating kinases, LATS1 and LATS2, in airway basal cells to understand how Hippo inactivity and subsequent YAP nuclear activity influences BC maintenance through its interaction with p63. Our preliminary data suggest that LATS1/2 deletion in Krt5 positive basal cells leads to basal cell hyperplasia and the formation of distinct populations of basal cells. Those adjacent to the basement membrane have the highest levels of nuclear p63, whereby this expression is reduced or lost in the Krt5+ cells that are more luminal in the hyperplastic lesion. Our studies further suggest that YAP activity in BCs is influenced by signals, such as FGF10, that come from stromal cells in the basement membrane, and we hypothesize that these signals influence YAP interactions with p63 to guide a BC self-renewal transcriptional program. We aim to unveil novel biochemical pathways that describe how signals from the basement membrane are transduced through BC receptor tyrosine kinases to increase YAP-p63 functional activity and BC self-renewal and growth. Specifically, we propose: 1) to determine if LATS1/2-depletion and subsequent YAP activation in airway basal cells influences BC maintenance through YAP-p63 interactions; 2) how signals from the basement membrane may promote these YAP/p63 interactions; and 3) if YAP-p63 complexes differentially regulate gene expression to promote BC fate. Ultimately this study will offer molecular insight into how BC self-renewal and expansion is regulated, which may offer directions for preventing BC expansion in disease or guide new methods to expand BCs ex vivo for regenerative therapy.


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: 2024 ( Subtotal = -$21,261 )
2024	2023	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	000	4	5/22/2024	NON-COMPETING CONTINUATION	-$21,261
														Subtotal = -$21,261

Issue Date FY: 2023 ( Subtotal = $31,847 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	001	4	3/14/2023	NON-COMPETING CONTINUATION	$471
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	000	4	12/23/2022	NON-COMPETING CONTINUATION	$31,376
														Subtotal = $31,847

Issue Date FY: 2022 ( Subtotal = $46,752 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	000	3	12/15/2021	NON-COMPETING CONTINUATION	$46,036
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	001	3	7/1/2022	NON-COMPETING CONTINUATION	$716
														Subtotal = $46,752

Issue Date FY: 2021 ( Subtotal = $46,036 )
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	001	2	3/15/2021	NON-COMPETING CONTINUATION	$516
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	000	2	12/23/2020	NON-COMPETING CONTINUATION	$45,520
														Subtotal = $46,036

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	000	1	1/14/2020	NEW	$0
2020	2019	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	001	1	1/14/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $45,016 )
2019	2019	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	000	1	8/23/2019	NEW	$45,016
														Subtotal = $45,016

Grand Total All Awards = $148,390

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Defining molecular signals that influence airway basal cell renewal and growth

Award Number: F31HL149381

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2023

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