# GSK3BETA, A MEDIATOR OF ETHANOL NEUROTOXICITY

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $338,011

## Abstract

Ethanol is a neuroteratogen and alcohol consumption during pregnancy causes Fetal Alcohol Spectrum
Disorders (FASD). FASD are currently the leading cause of mental retardation in North America. The most
devastating effect of developmental exposure to ethanol is the loss of CNS neurons which underlie many
behavioral deficits observed in FASD. We demonstrated that ethanol caused both oxidative stress and
endoplasmic reticulum (ER) stress in the developing brain. We showed that ethanol induced the expression of
monocyte chemoattractant protein-1 (MCP-1) and a specific ER stress-inducible protein, mesencephalic
astrocyte-derived neurotrophic factor (MANF). Our studies suggested that both MCP-1 and MANF were
involved in ethanol-induced ER stress and neuron death. The central hypothesis for this proposal is that
ethanol-induced neurodegeneration in the developing brain is mediated by the interplay of oxidative stress and
ER stress. Three corollary hypotheses will be tested: 1) ethanol-mediated oxidative stress causes an early
neuron death; the second phase of neuron death is mainly mediated by ethanol-induced ER stress or a
combined action of both oxidative stress and ER stress; 2) the oxidative stress-induced neuron death is mainly
regulated by the mitochondrial intrinsic apoptotic pathway; while the ER stress-induced neuron death is
mediated by the GSK3β/calpain/caspase7/12 pathway; 3) activation of MCP-1 mediated signaling potentiates
ethanol-induced ER stress and promotes an ER stress-initiated apoptotic program in neurons; contrarily,
MANF is a neuroprotective protein which alleviates ethanol-induced ER stress and neuron death. We propose
three specific aims to test these hypotheses. Specific Aim 1 will test the hypothesis that ethanol-induced
neuron death is caused by the interplay of oxidative stress and ER stress in vitro. Specific Aim 2 will
determine the role of MCP-1 signaling and MANF in ethanol-induced ER stress and neuron death in the
developing brain. Specific Aim 3 will determine whether simultaneous inhibition of oxidative stress and ER
stress offers maximal protection and improves behavioral deficits in mice. As a unit, this proposal will
systematically investigate the interplay of oxidative stress and ER stress and assess their contribution to
ethanol-induced neuron death. This study will therefore not only provide novel insight into the mechanisms of
ethanol-induced damage to the developing CNS but also identify specific targets for developing effective
therapeutic strategies.

## Key facts

- **NIH application ID:** 10249516
- **Project number:** 7R01AA015407-17
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** JIA LUO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $338,011
- **Award type:** 7
- **Project period:** 2004-12-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249516

## Citation

> US National Institutes of Health, RePORTER application 10249516, GSK3BETA, A MEDIATOR OF ETHANOL NEUROTOXICITY (7R01AA015407-17). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10249516. Licensed CC0.

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