# Cellular and genomic mechanisms of the impact of ethanol on human neural model

> **NIH NIH R01** · RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL · 2022 · $561,319

## Abstract

Abstract and summary
Alcohol use disorders (AUD) are complex behaviors accompanied by substantial morbidity, mortality and societal
expense. Both genetic and environmental factors contribute to AUD. Despite progress in the human genetics of
AUD, especially the identification of genome-wide significant AUD genetic risk variants, the neural basis of AUD
in humans is largely unknown. Over the past five years, we have provided compelling evidence that: 1) Human
neuronal cells derived from induced pluripotent stem (iPS) cells can be used as a tractable model to study
neuropsychiatric disorders including AUD; 2) Ethanol exposure results in an inflammasome response in human
neurons; 3) Human neurons carrying OPRM1 A118G minor gene variants showed enhanced sensitivity to
opioids and ethanol; 4) Ethanol causes gene expression changes in both human neurons and glial cells; and 5)
Microglia-containing 3D neural cultures can be a powerful system to study neuroinflammatory microglia-neuronal
interactions. These premises provide a foundation for further mechanistic studies of the genetic and molecular
underpinnings of AUD in human iPS cell-derived neural models. We also identified key gaps of knowledge in
utilizing human neurons as a model system to study AUD that need to be filled, particularly: 1) how ethanol
affects neuro-glial interactions in a human neural context is not known; and 2) how ethanol affects neurogenesis
in a 3D context is not known. Moreover, 3) because of the polygenic nature of AUD, the contribution of single
gene to AUD risk is likely small and the phenotypical manifestation is strongly influenced by individual’s genetic
makeup. To address these outstanding questions, we hypothesize that ethanol impairs neuronal function via
affecting neuroglial interactions, which is influenced by individual polygenic risk backgrounds. We have selected
36 subjects of both sexes with either extremely high polygenic risk score (PRS, top 10%ile, n=18 AUD) or low
PRS (bottom 10%ile, n=18, no AUD) to test this hypothesis. We will differentiate iPS cells derived from these
subjects into both 2D and 3D (i.e. brain organoids) neuronal cells co-cultured with human astrocytes and human
microglia. Upon exposure to ethanol, these neural cells are subjected to a combination of morphological,
immunocytochemical, electrophysiological, live cell imaging and genomic analyses to unravel the mechanism(s)
underlying the impact of ethanol, focusing on neuro-astro-microglial interactions. In a relatively large collection
of human iPS cells (n=36 lines) derived from subjects with extreme AUD PRSs, we hope to unravel the
convergent phenotype and gene-networks that are linked to extreme high or low AUD PRSs. The results will
advance our mechanistic understanding of the pathogenic role of AUD risk gene variants and the influence of
polygenic risk background in a human neural system.

## Key facts

- **NIH application ID:** 10453317
- **Project number:** 2R01AA023797-06A1
- **Recipient organization:** RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
- **Principal Investigator:** ZHIPING P. PANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $561,319
- **Award type:** 2
- **Project period:** 2016-02-05 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10453317

## Citation

> US National Institutes of Health, RePORTER application 10453317, Cellular and genomic mechanisms of the impact of ethanol on human neural model (2R01AA023797-06A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10453317. Licensed CC0.

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