# Cellular Mechanisms in Fetal Alcohol Spectrum Disorders

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $643,197

## Abstract

Project Summary/Abstract
Alcohol (ethanol) exposure during pregnancy is the leading environmental cause of birth defects and central
nervous system dysfunction. While the effects of ethanol on the brain and face have been explored quite
extensively, there is a considerable lack of knowledge regarding the pathogenic mechanisms of developmental
ethanol exposure. A significant amount of work over the years, including from our lab, has demonstrated that
apoptosis is associated with prenatal ethanol exposure. However, apoptosis cannot account for all of the effects
associated with fetal alcohol spectrum disorders (FASD). Previous work on this project has demonstrated that
one non-apoptotic pathogenic mechanism involves the primary cilia. Primary cilia are small hair-like organelles
that are present on almost every cell and are critical for normal development and cellular homeostasis. Genetic
disruptions in primary cilia function have been increasingly explored over the last several years and are classified
under the term ciliopathies. Recent work from our lab has demonstrated that prenatal ethanol exposure can also
temporarily disrupt primary cilia function resulting in a “transient ciliopathy” with a particularly devastating effect
on the Sonic hedgehog (Shh) pathway. However, the cellular mechanism by which ethanol acts at the cilium is
unclear. In this current proposal, we will further explore these mechanisms using a variety of tools and cross-
sectional approaches. In Aim 1, we will test whether ethanol is affecting transport along the microtubule axoneme
within the primary cilium or transport into or out of the primary cilia compartment. Both of these ciliary functions
are vital to normal cilia function and will be probed using a variety of in vitro and in vivo techniques in wild type
and transgenic mouse lines. In Aim 2, we will take advantage of the convergent effects of ethanol and
cannabinoids on primary cilia to explore the role of ethanol in modulating G-protein coupled receptor (GPCR)
signaling. Several GPCRs, including those in the Shh and cannabinoid pathways signal through primary cilia
and this aim will test how ethanol affects these key receptors. Aim 3 will leverage targeted small molecule
screens to identify novel pathways of ethanol's pathogenic mechanisms. Using a combination of high-throughput
in vitro assays and in vivo confirmation, we will identify novel targets of developmental ethanol exposure.
Collectively, these experiments will greatly increase our knowledge of ethanol's mechanisms of actions in the
developing embryo, with important implications for informing clinical research studies and prevention and
intervention strategies as well.

## Key facts

- **NIH application ID:** 11049325
- **Project number:** 2R01AA026068-06A1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Scott Parnell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $643,197
- **Award type:** 2
- **Project period:** 2018-12-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11049325

## Citation

> US National Institutes of Health, RePORTER application 11049325, Cellular Mechanisms in Fetal Alcohol Spectrum Disorders (2R01AA026068-06A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11049325. Licensed CC0.

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