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The multi-organ role of NETs in alcohol-induced ACLF

Award Number: K99AA032847
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/17/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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The multi-organ role of NETs in alcohol-induced ACLF - PROJECT SUMMARY/ABSTRACT The Candidate is a postdoctoral fellow committed to developing an academic research group focused on applying proteomics to understand inter-organ crosstalk in alcohol-induced acute-on-chronic liver failure (aACLF). His previous and current work has given him the unique skillset to answer questions involving the development of chronic liver disease and the activation in the immune system, specifically neutrophils. The Career Development Plan describes 2 years of mentored research wherein the candidate will develop skills in immunology, generate the proteomic data outlined in the proposal, and learn leadership skills to transition into independence. During the R00 phase, he will develop new experimental designs (organ-on-chip) and apply proteomic analysis to understand how the secretome from NET-damaged hepatocytes regulate renal epithelial cells in aACLF. This will allow the candidate to establish future projects on the effect of alcohol and NETs at a multi-organ level. Research Plan: ACLF is a recently defined syndrome characterized by poor survival and multi- organ dysfunction/failure. Alcohol is known to be the most common trigger of ACLF. Current therapies for ACLF patients are limited to organ transplantation; In order to increase the therapeutic options for these patients, we recently developed a novel mouse model of ACLF induced by alcohol. Taking advantage of this model, which mimics human ACLF, we identified the production of NETs (web-like structures made from decondensed DNA and proteins that neutrophils produce to neutralize microbes) as a novel key mechanism in ACLF pathophysiology. Two types on NETosis have been recently described; vital versus suicidal, with the latter one leading to higher production of NETs and neutrophil death. We hypothesize that alcohol induces suicidal over vital NETosis, which might directly damage hepatocytes and renal epithelial cells. We also believe that NETs activate hepatocytes that in turn contribute to kidney damage by impairing the production of protective mediators such as HGF to the kidney, overall impairing hepatorenal function in aACLF. In this proposal, we will: First, use neutrophils isolated from aACLF patients or healthy neutrophils stimulated with alcohol ex vivo to determine the effect of alcohol in modulating NETosis subtypes (suicidal vs vital) and NET components (DNA and proteins). Second, we will isolate cell-free NETs from healthy controls or aACLF patients and co-culture them with primary human hepatocytes to assess the direct effect of NETs on hepatocyte function and phenotype. We will also inhibit NET formation in vivo in a preclinical model of aACLF to potentially improve hepatocyte and liver function. Third, because kidney failure is frequently observed in ACLF patients, we will dissect the direct role of NETs in kidney cells and determine (using mass spectrometry learned in the K99 phase), which mediators secreted by hepatocytes regulate renal epithelial cell phenotype in the context of aACLF. Altogether, this proposal will widen our understanding on how alcohol regulates NETs, assess the effect of NETs at a multi-organ level in the context of aACLF and identify potential new therapeutic targets to ameliorate liver and kidney dysfunction in aACLF.


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 = $177,736 )
2026	2026	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Alcohol Research Programs	000	1	8/20/2026	NEW	$177,736
														Subtotal = $177,736

Grand Total All Awards = $177,736

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The multi-organ role of NETs in alcohol-induced ACLF

Award Number: K99AA032847

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/17/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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