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Alcohol-mediated Clock genes interfere with lung injury and repair

Award Number: R01AA029690
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2023
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Alcohol-mediated Clock genes interfere with lung injury and repair - In the United States, the acute respiratory distress syndrome (ARDS) remains a significant public health problem. Despite substantial efforts to improve the outcome, ~ 80% of ARDS survivors experience reduced health-related quality of life and have fibrotic changes on chest imaging for up to 5 years after diagnosis. Chronic alcohol abuse significantly increases the incidence of, and mortality from, ARDS, without directly causing lung damage. Emerging data show that alcohol interferes with the circadian signaling pathway in the liver and intestine which, in turn, render tissue susceptibility to injury and fibrosis. The circadian pathway consists of multiple transcription factors which mediate various organ physiological functions through its regulatory networks. It is known that some of circadian pathway molecules can regulate non-coding RNAs and vice versa, non-coding RNAs can regulate circadian pathway molecules. In this proposal, we present preliminary data showing that alcohol promotes circadian pathway dysfunction in the lung through alterations of circadian pathway molecules BMAL1 and nuclear factor Retinoid-Related Orphan Receptor-alpha (RORα). We believe these changes lead to alcohol-induced TGFβ1 by suppressing RORα-miR-139 activity. Further, we identified the circ-RORα-miR-155 axis as a novel regulatory mechanism of BMAL1. These results led us to hypothesize that chronic alcohol ingestion disrupts circadian pathway signaling and the circ-RORα-miR-155 axis which, thereby perturbing the RORα-miR-139 axis which, in turn, render lung susceptibility toward fibroproliferative disrepair following acute injury. The experimental approaches are designed to test this hypothesis. These studies will provide a firm scientific basis for the underlying mechanisms by which alcohol interferes with tissue repair following lung injury.


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 = $493,215 )
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Alcohol Research Programs	000	3	5/15/2025	NON-COMPETING CONTINUATION	$493,215
														Subtotal = $493,215

Issue Date FY: 2024 ( Subtotal = $491,796 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Alcohol Research Programs	000	2	2/27/2024	NON-COMPETING CONTINUATION	$442,616
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Alcohol Research Programs	001	2	5/16/2024	NON-COMPETING CONTINUATION	$49,180
														Subtotal = $491,796

Issue Date FY: 2023 ( Subtotal = $525,113 )
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Alcohol Research Programs	000	1	3/14/2023	NEW	$525,113
														Subtotal = $525,113

Grand Total All Awards = $1,510,124

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Alcohol-mediated Clock genes interfere with lung injury and repair

Award Number: R01AA029690

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/15/2023

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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