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Epigenetic Regulation of the Maturation and Function of Lung Epithelium by the SWI/SNF Proteins ARID1A and ARID1B.

Award Number: R01HL156860
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/20/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Epigenetic Regulation of the Maturation and Function of Lung Epithelium by the SWI/SNF Proteins ARID1A and ARID1B. - PROJECT SUMMARY: It is being increasingly recognized that changes in chromatin state are associated with a wide spectrum of lung diseases, ranging from bronchopulmonary dysplasia (BPD) to chronic obstructive pulmonary disease (COPD). However, the mechanisms by which these changes contribute to the pathogenesis of these diseases, and how to manipulate the epigenome for therapeutic benefit, remains largely unknown. Modulation of chromatin accessibility is an important epigenetic mechanism by which gene expression is controlled, even across repeated cell divisions. However, as a prerequisite to understanding how altered chromatin accessibility contributes to disease, the mechanisms by which chromatin accessibility patterns first establish and maintain cellular identity within the lung must be defined. This proposal is based on studies from our group that identified the SWI/SNF proteins Arid1a and Arid1b as key mediators of the chromatin accessibility changes that occur during development of the SOX9+ lung epithelial stem/progenitor cell population. Our data demonstrate that loss of Arid1a or Arid1b led to persistence of the SOX9+ progenitor cell population, impaired alveolar differentiation, and neonatal death due to respiratory distress. In addition, ARID1A directly interacts with NKX2-1 and SOX9. The central hypothesis of the present proposal is that ARID1A and ARID1B interact with key lung developmental TFs to direct the SWI/SNF complex to remodel chromatin at specific loci, silencing progenitor cell gene expression programs and promoting the maturation and function of the mature alveolar epithelium. The proposed studies will: A) Define the role that Arid1a/Arid1b, and the larger SWI/SNF complex, play in establishment of mature alveolar cell type identify in mouse and human. B) Identify the mechanism(s) by which the SWI/SNF complex remodels chromatin, in conjunction with key lung transcription factors, to establish and maintain gene expression modules controlling type I & II AEC identity and function. C) Determine how Arid1a/Arid1b-mediated chromatin remodeling contributes to the lung epithelial repair response following influenza infection. These studies will provide conceptual advances in our understanding of how mature alveolar epithelial cells are established and maintained, how the chromatin accessibility landscape interacts with previously well- defined transcription factor networks, and how chromatin remodeling directs the normal repair process after lung injury. Emerging epigenomic tools and systems biology approaches will be applied to the epithelium for the first time. Taken together, these data will inform future translational studies seeking to understand how alterations in the epigenome contribute to lung disease, and will provide a foundation for future efforts to manipulate the lung’s epigenomic code to restore normal lung structure and function.


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 = $357,750 )
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	001	5	7/15/2025	NON-COMPETING CONTINUATION	$357,750
2025	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	4	6/4/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $357,750

Issue Date FY: 2024 ( Subtotal = $427,845 )
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	4	4/30/2024	NON-COMPETING CONTINUATION	$357,750
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	001	4	9/1/2024	SUPPLEMENT FOR EXPANSION	$70,095
														Subtotal = $427,845

Issue Date FY: 2023 ( Subtotal = $357,750 )
2023	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	001	3	8/9/2023	NON-COMPETING CONTINUATION	$0
2023	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	3	4/21/2023	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $357,750

Issue Date FY: 2022 ( Subtotal = $357,750 )
2022	2022	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	2	4/30/2022	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $357,750

Issue Date FY: 2021 ( Subtotal = $357,750 )
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	001	1	6/23/2021	NEW	$35,775
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	1	5/17/2021	NEW	$321,975
														Subtotal = $357,750

Grand Total All Awards = $1,858,845

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Epigenetic Regulation of the Maturation and Function of Lung Epithelium by the SWI/SNF Proteins ARID1A and ARID1B.

Award Number: R01HL156860

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/20/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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