# Defining the metabolic-epigenetic regulation of neuronal chromatin by alcohol

> **NIH NIH K99** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $155,576

## Abstract

Project Summary
Addiction to alcohol represents a major public health issue exacting tremendous financial and social costs.
Despite this, alcohol addiction remains a recalcitrant condition with conventional pharmacotherapies lacking
substantial and durable efficacy. Much of the existing research into the neurobiology and treatment of alcohol
addiction has focused on limbic reward circuitry, changes in neurotransmission, and intracellular neuronal
signaling cascades. However, in recent years there has been a surge in research examining the role of epigenetic
factors in the development of pathological alcohol use disorders. Epigenetic control of gene expression plays a
critical role in processing neural activity in the adult brain, and there is clear evidence in humans and animal
models that link changes in brain chromatin to addiction. In recent years, chromatin-bound metabolic enzymes
have emerged as central players in epigenetic regulation, leading to a fundamental shift in models of
transcriptional regulation, and implicating epigenetic-metabolic processes in the molecular and behavioral
response to alcohol. This NIH Pathway to Independence Award (K99/R00) will significantly facilitate the
candidate’s, Dr. Mews, ability to begin his career as an independent scientist, allowing him to study new
perspectives of this metabolic-epigenetic gene regulation by alcohol, and to explore epigenetic factors as novel
therapeutic targets in alcohol use disorders. In the mentored K-phase of this grant (Specific Aim 1 and Specific
Aim 2), the contribution of peripheral alcohol metabolism in the liver to histone acetylation in the brain will be
determined in a translationally relevant binge drinking model in rodents. Alcohol-induced histone acetylation will
be assayed both locally and globally in the hippocampus, a region intimately linked to alcohol addiction
vulnerability, and the direct modulation of gene expression by alcohol-derived acetate that originates in hepatic
alcohol metabolism will be tested. Further, viral manipulation of gene expression to manipulate acetyl-CoA
metabolism will be used to establish causality and determine whether the metabolic-epigenetic ACSS2 pathway
links alcohol-driven histone acetylation to increased consumption and alcohol-related learning. In the
independent phase (R00), Specific Aim 3, we will combine these conceptually and technically innovative
approaches with translational binge drinking models to investigate the chromatin-based targeting mechanisms
that allow ACSS2 to regulate specific gene expression induced by alcohol in the brain. In summary, the research
proposed in this Pathway to Independence Award will illuminate the metabolic-epigenetic mechanisms by which
alcohol influences neuronal processes as well as alcohol-related learning and drinking behavior; while
simultaneously preparing the candidate with an unique set of intellectual and technical skills that will allow him
to develop a fully independent research p...

## Key facts

- **NIH application ID:** 10054232
- **Project number:** 1K99AA027839-01A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Philipp Mews
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $155,576
- **Award type:** 1
- **Project period:** 2020-08-05 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10054232

## Citation

> US National Institutes of Health, RePORTER application 10054232, Defining the metabolic-epigenetic regulation of neuronal chromatin by alcohol (1K99AA027839-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10054232. Licensed CC0.

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