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Vagus nerve and cholinergic anti-inflammation in the pathogenesis of alcohol-associated liver disease

Award Number: R01AA032837
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: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Vagus nerve and cholinergic anti-inflammation in the pathogenesis of alcohol-associated liver disease - PROJECT SUMMARY Alcohol abuse has become a serious health concern worldwide. Alcohol-associated liver disease (ALD) is characterized by elevated circulating levels of lipopolysaccharide (LPS) and pro-inflammatory cytokines in human subjects and experimental animal models. ALD is one of the most common indications for liver transplantation. However, effective anti-ALD treatment is still lacking. As an FDA-approved therapeutic approach in treating patients with drug-resistant epilepsy and major depression, left cervical vagus nerve stimulation (VNS) also shows beneficial effects on a variety of diseases that are associated with enhanced immune response. Specifically, VNS attenuates obesity-induced liver damage in rodents. These findings led us to investigate whether VNS has a protective effect on ALD pathogenesis. Interestingly, we found that VNS-treated rats exhibited attenuated circulating ALT and reduced hepatic inflammation. Currently, the established mechanism of vagus nerve mediated-cholinergic anti-inflammatory pathway highlights the essential role of splenic macrophages in disease development. These macrophages express α7 nicotinic acetylcholine receptor (α7nAChR or Chrna7). Activation of Chrna7 by agonists suppresses LPS-induced inflammatory cytokine production from cultured macrophages and Kupffer cells. Notably, Kupffer cells and infiltrating macrophages are critical contributing factors to the pathogenesis of ALD via regulating local and systemic inflammatory responses. However, it remains unknown whether and how Chrna7-expressing immune cells modulate ALD. Interestingly, our preliminary data showed that Chrna7 agonist treatment ameliorated alcohol-induced liver injury, accompanied by reduced hepatic inflammatory response. In addition, Kupffer cell Chrna7 deficiency protects against whereas myeloid cell Chrna7 ablation exacerbates ALD in mice. In Aim 1, we will determine the underlying mechanisms by which VNS and Chrna7 agonist attenuate alcoholic liver damage. In Aim 2, we will delineate the distinct role of Chrna7-expressing Kupffer cells and macrophages in ALD. The successful accomplishment of the proposed experiments will fill the gap of knowledge and facilitate the development of new therapies in ALD treatment.


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 = $555,966 )
2026	2026	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Alcohol Research Programs	000	1	8/25/2026	NEW	$555,966
														Subtotal = $555,966

Grand Total All Awards = $555,966

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Vagus nerve and cholinergic anti-inflammation in the pathogenesis of alcohol-associated liver disease

Award Number: R01AA032837

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: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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