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Regulation of Ductular Reaction by Substance P during Alcohol-induced Liver Injury

Award Number: R21AA030095
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: 04/01/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Regulation of Ductular Reaction by Substance P during Alcohol-induced Liver Injury - Alcohol-associated liver disease (ALD) is one of the leading causes of chronic liver disease in Western countries. ALD is associated with increased mortality due to a broad spectrum of hepatic pathologies ranging from simple steatosis to alcoholic steatohepatitis (ASH), alcoholic hepatitis (AH), cirrhosis, and hepatocellular carcinoma. Recent studies have drawn attention to other factors contributing to ALD, including alterations in the vasculature, portal tract inflammation and peribiliary fibrosis, and ductular reaction (i.e., activation of the neuroendocrine phenotype of cholangiocytes). However, very little information is known about the effects of alcohol on biliary epithelial cells (i.e., cholangiocytes). Substance P (SP) is a neuropeptide secreted predominantly from sensory neurons and is known to play a key role in neuroinflammation via the recruitment and activation of immune cells. Previous studies have shown an upregulation of the SP/NK1R axis in cholangiocytes in response to liver injury due to cholestasis and that SP regulates cholangiocyte proliferation via cAMP/PKA signaling. SP has been shown to increase hepatic fibrosis via differential changes in cholangiocytes and hepatic stellate cell (HSCs) senescence. However, the SP/NK1R axis's role in ALD has not been explored. Based on novel preliminary data, the central hypothesis is that ALD-induced ductular reaction triggers a neuroendocrine phenotype in cholangiocytes whereby secretion of SP stimulates hepatic steatosis and fibrosis and increases infiltration and activation of immune cells occurs during the progression of ALD in proposed. To address the central hypothesis, two specific aims are proposed: 1) determine the expression and distribution of SP/NK1R axis during the progression of ALD in human samples and a mouse model of alcohol- induced liver injury; and 2) determine the therapeutic potential of the knockdown and/or pharmacological inhibition of the SP/NK1R axis in a mouse model of ALD and human ALD-derived liver organoids. The expected outcome of this work is an understanding of the role of the SP/NK1 axis and downstream signaling mechanisms in the pathogenesis of ALD. The successful completion of the proposed studies will have a significant positive impact on the knowledge of factors regulating ductular reaction observed in ALD and lay the groundwork for developing novel therapeutic approaches for ALD.


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 = $0 )
2026	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Alcohol Research Programs	000	2	2/6/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $186,865 )
2024	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Alcohol Research Programs	001	2	5/21/2024	NON-COMPETING CONTINUATION	$18,686
2024	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Alcohol Research Programs	000	2	4/15/2024	NON-COMPETING CONTINUATION	$168,179
														Subtotal = $186,865

Issue Date FY: 2023 ( Subtotal = $236,912 )
2023	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Alcohol Research Programs	000	1	3/28/2023	NEW	$236,912
														Subtotal = $236,912

Grand Total All Awards = $423,777

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Regulation of Ductular Reaction by Substance P during Alcohol-induced Liver Injury

Award Number: R21AA030095

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: 04/01/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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