# Project 2: Prenatal Alcohol Exposure (PAE) and Fetal Alcohol Spectrum Disorder (FASD)

> **NIH NIH U54** · NORTH CAROLINA CENTRAL UNIVERSITY · 2022 · $186,458

## Abstract

Project Summary
The objective of the proposed research is to target molecular pathways involved in alcohol-induced limb/fin
defects to identify novel mechanisms with a role in FASD with the long-term goals of informing clinical practice,
and ultimately reducing the incidence and severity of Fetal Alcohol Spectrum Disorders (FASD). This objective
will be met by applying two innovative and complementary approaches that use cell, zebrafish and mouse
models to (i) genetically knockout and identify genes that rescue or exacerbate the effects of ethanol exposure,
and (ii) high throughput screening of focused chemical libraries to identify compounds that modulate the effects
of ethanol exposure. Our approach utilizes genetically modified zebrafish and mice, and the developing fin and
limb respectively, as readily examined target tissues whose molecular signaling pathways and vulnerability to
ethanol teratogenesis are well documented. This research proposal is founded on 1) strong evidence that
craniofacial abnormalities and limb defects have been observed in those identified with FASD, 2) recognition
that disruption of sonic hedgehog (Shh) signaling, a major morphogenic pathway regulating embryonic
development as a significant consequence of prenatal ethanol exposure (PAE), 3) that genetically reduced
Shh signaling results in increased vulnerability to ethanol-induced birth defects, and 4) the availability of
differentially expressed gene sets from our previous study on the effects of PAE on mouse limb development.
The hypothesis to be tested is that the identification of novel genes and compounds that can rescue
morphological and behavioral deficits elicited by PAE will reveal fundamental and novel insights into the
mechanism of ethanol-induced birth defects. This hypothesis will be tested with experiments that employ well-
established cell line, zebrafish, and mouse FASD models and will address the following Specific Aims: Aim 1
will use these in vivo and in vitro models to assess gene-environment interactions, particularly the candidate
genes whose expression was shown to be altered in ethanol-exposed mouse limb buds by our previous
ethanol RNA Seq study. Aim 2 is to utilize high-throughput screening technologies in vitro and in vivo to identify
small molecule modulators that rescue or exacerbate the effects of PAE. Small molecule compounds that
rescue or exacerbate ethanol-induced fin defects in zebrafish embryos and limbs defects in mice will be
identified. The proposed studies will be conducted by NCCU faculty and trainees under the mentorship of
UNC’s Bowles Center for Alcohol Studies researchers. In addition to expanding our understanding of ethanol’s
teratogenic mechanism of action as well as providing clues regarding genetic sensitivities and interventions for
FASD and potentially novel pathways with a role in FASD, this research project will foster state of the art
research by budding scientists from underrepresented minorities and will provi...

## Key facts

- **NIH application ID:** 10540966
- **Project number:** 1U54AA030451-01
- **Recipient organization:** NORTH CAROLINA CENTRAL UNIVERSITY
- **Principal Investigator:** Kevin Peter Williams
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $186,458
- **Award type:** 1
- **Project period:** 2022-09-20 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10540966

## Citation

> US National Institutes of Health, RePORTER application 10540966, Project 2: Prenatal Alcohol Exposure (PAE) and Fetal Alcohol Spectrum Disorder (FASD) (1U54AA030451-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10540966. Licensed CC0.

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