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Role of Intestinal Autophagy in the Pathogenesis of Alcohol Associated Liver Disease

Award Number: R01AA030571
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: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Role of Intestinal Autophagy in the Pathogenesis of Alcohol Associated Liver Disease - Abstract: Alcohol-Associated Liver Disease (ALD) continues to be a major cause of morbidity and mortality worldwide. Currently, there are no FDA-approved therapies that block or reverse ALD progression. Understanding the key steps that promote ALD progression is essential to identifying new treatment targets and methods that alleviate ALD. Prominent among the factors that contribute to ALD progression is the alcohol-induced disruption of intestinal barrier integrity, accompanied by microbial flora imbalance (dysbiosis). Both these promote gut and liver injury. However, the cellular/molecular mechanisms by which excessive drinking triggers dysbiosis and compromises intestinal barrier integrity must be clearly established. Here, we present unique, exciting new data, showing that chronic ethanol (EtOH) feeding disrupts intestinal autophagy, a crucial intracellular catabolic process that begins with the formation of autophagosomes (AV), which sequester and deliver senescent macromolecules and organelles to lysosomes for breakdown in this organelle. The degraded species are replenished by synthesis. This process of rapid and constant turnover preserves the specialized functions of all cells, but especially intestinal cells and it regulates intestinal microbial composition as well, thereby, maintaining gut homeostasis. Our understanding of autophagy’s role in preserving intestinal barrier function has progressed significantly, but we need a better understanding of how EtOH misuse disrupts gut autophagy to impair barrier function. Our objective is to ascertain the mechanism(s) by which EtOH exposure dysregulates autophagy in intestinal cells to compromise gut barrier integrity and promotes alcohol-induced liver injury. We propose the following Specific Aims: Aim 1. Investigate how EtOH-induced lysosome disruption affects epithelial cell barrier integrity; Aim 2) Clarify the effects of EtOH-induced autophagy disruption on Paneth cell function and Aim 3) Ascertain how EtOH-induced liver injury is exacerbated by deficient intestinal autophagy but is alleviated by autophagy reactivation in the gut.


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 = $471,559 )
2025	2025	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Alcohol Research Programs	000	3	5/12/2025	NON-COMPETING CONTINUATION	$471,559
														Subtotal = $471,559

Issue Date FY: 2024 ( Subtotal = $483,388 )
2024	2024	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Alcohol Research Programs	005	2	7/31/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$483,388
2024	2024	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Alcohol Research Programs	001	2	3/29/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$483,388
2024	2024	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Alcohol Research Programs	003	2	6/18/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$456,806
2024	2024	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Alcohol Research Programs	004	2	7/29/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$483,388
2024	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Alcohol Research Programs	000	1	3/28/2024	NEW	$0
2024	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Alcohol Research Programs	002	1	6/18/2024	NEW	-$456,806
														Subtotal = $483,388

Issue Date FY: 2023 ( Subtotal = $500,255 )
2023	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Alcohol Research Programs	000	1	6/26/2023	NEW	$500,255
														Subtotal = $500,255

Grand Total All Awards = $1,455,202

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Role of Intestinal Autophagy in the Pathogenesis of Alcohol Associated Liver Disease

Award Number: R01AA030571

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: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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