A translational approach for novel precision medicine models

This Project Grant, awarded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) under the Alcohol Research Programs (CFDA 93.273), supports translational research to identify novel molecular targets and mechanisms of treatment responses in alcohol use disorder (AUD). The $3.17 million award to New York University School of Medicine, funded from September 10, 2025, through August 31, 2029, focuses on elucidating the role of mitochondrial metabolism—specifically lactate (LAC) production via the CRAT enzyme—in epigenetic regulation and treatment response in AUD. The research team will deliver preclinical and clinical research products examining baseline and longitudinal changes in central mitochondrial LAC metabolism, mapping the topographical and cellular specificity of these changes, and identifying biomarkers (including cognitive impulsivity) that predict treatment response. These deliverables aim to establish the mechanistic linkage between CRAT expression in neuronal exosomes, histone acetyltransferase activity, and gene expression patterns associated with improved cognitive function and reduced heavy drinking in AUD patients.

The collaborative research initiative includes a federal sub-award to the Research Foundation For Mental Hygiene, Inc. (Nathan S. Kline Institute for Psychiatric Research), effective December 24, 2025. This partnership leverages specialized neuroscience research capabilities to advance understanding of mitochondrial metabolism and epigenetic mechanisms in AUD, contributing to the development of precision medicine models and therapeutic targets that could improve treatment strategies and clinical outcomes for individuals with alcohol use disorder.

Abstract

This collaborative proposal aims to identify novel molecular targets and mechanisms of treatment responses in AUD based on the evolving knowledge of a novel mitochondrial mechanism of epigenetic regulation and therapeutic target for AUD. Our cumulative findings and work from others showed: 1) administration of LAC, a pivotal mitochondrial metabolite synthesized by the mitochondrial enzyme crat, ameliorates executive function, which is affected in AUD, and leads to the activation of specific hats with the corresponding up-regulation of key genes (bdnf, MGLU2) in the hippocampus and ventral striatum, which are substrates implicated in AUD. 2) LAC also protects against AUD-related oxidative stress and neuroinflammation.3)in AUD patients, LAC reduces heavy drinking days and ameliorates cognitive function.yet, the targets and mechanisms by which LAC-related mitochondrial metabolism contributes to the epigenetic regulation of treatment responses in AUD are unknown. Based on these compelling preclinical and clinical findings, we set out to test the central hypothesis that, by facilitating LAC-related activity of hats, expression of crat in neuronal exosomes contribute to gexr response in AUD. We have exciting preliminary data: I)lowest crat expression in these specific exosomes, worst cognitive dysfunction; II)potential role of mitochondrial metabolism in HAT activity; III)specific baseline traits, including cognitive impulsivity, predict gexr response; IV)potential role of this novel signaling pathway in gexr response. Aims:1)determine the role of baseline and longitudinal changes in central mitochondrial metabolism of LAC for treatment response; 2) determine the role of central mitochondrial metabolism of LAC in the epigenetic regulation of gene expression for treatment responses in AUD; we will further map topographical and cellular specificity of changes. In addition to the primary features of this mitochondrial signaling, we will assess a broader set of related mitochondrial, epigenetic and transcriptomic markers focusing on oxidative stress, glutamate, neurotrophic and inflammatory pathways in neuronal exosomes isolated from plasma of AUD subjects from the niaaa-sponsored randomized controlled trial of gabapentin enacarbil extended-release (gexr, N=338). Utilizing mixed effect models, machine learning and clustering algorithms, we will model the separate and combined features of the primary and related pathways in predicting changes in heavy drinking days unadjusted for likelihood of responding to gexr (primary analysis) and separately in causal inference models of likely responders. This study will also determine the relationship between central and peripheral molecular pathways of interest (peripheral rnaseq, samples and clinical characteristics are already available in our newest niaaa-funded R01, PI marmar), and how these pathways are modified by specific known AUD comorbidities. This contribution is significant as IT will advance understanding of mechanisms and targets of AUD treatment and identify critical SEX differences. Mechanistic insights into central and peripheral markers of gexr response is impactful as they will aid to develop new treatment models targeted at endogenously adjusting mitochondrial metabolism to function within the epigenetic milieu for personalized AUD treatment. This proposal is also innovative as we use innovative approaches that we are using in other NIH-funded studies to link in vivo molecular targets and pathways to treatment responses over-time. We have a published track record in this area.