# Dynamic neuroimmune interactions in the onset and progression of FASD

> **NIH NIH R01** · UNIV OF ARKANSAS FOR MED SCIS · 2020 · $451,350

## Abstract

PROJECT SUMMARY
Fetal alcohol spectrum disorders (FASD) and associated neurologic sequelae occur in almost 5% of children in
the U.S. – the deficits are life-long – and there is no cure. The goal of the proposed studies is to define the
dynamic roles of microglia and astrocytes in ethanol-induced neuroinflammation and neuropathology in FASD.
Ethanol-induced neuroinflammation in the developing CNS is believed to contribute to the long-term sequelae
associated with FASD. However, critical gaps in knowledge remain concerning the dynamic interactions
between microglia, astrocytes and neurons which mediate the transition from normal CNS development to
FASD neuropathology. Furthermore, the cellular and molecular mechanisms mediating transition to and
progression of the neuropathology have not been elucidated, which prevents targeted treatment. The proposed
studies directly address these critical gaps in knowledge. Hypothesis: Alcohol exposure in the developing CNS
elicits neuroimmune activation of microglia and astrocytes which disrupts normal dynamic interactions between
these glial cells and neurons during onset and progression of FASD, producing neuropathology. Further,
elucidating molecular mechanisms (currently unexplored) that regulate ethanol-induced neuroinflammation,
neuron loss, and alterations in normal glia-neuron interactions will reveal therapeutic targets for FASD. Aim 1.
Determine the dynamic role of microglia and astrocytes in the transition from normal cerebellar development to
ethanol-induced neuropathology and progression of FASD. (SubAim A) Evaluate changes in cell-cell
interactions between microglia, astrocytes, and neurons visualized at the level of glial processes and neuronal
dendrites, spines, and somas. This will be done with high resolution 3D reconstructions. Define and compare
the temporal pattern of neuroinflammation and neuron loss following ethanol exposure. Neuroinflammation will
be assessed by glial activation and by directed qRT-PCR arrays and multiplex protein arrays of immune
molecules. Purkinje neuron loss will be assessed by unbiased stereology. (SubAim B) Probe dynamic changes
in the transcriptome using unbiased RNA-Seq and bioinformatic analyses. Analyses will be performed on the
whole cerebellum as well as purified glia and neurons. (SubAim C) Examine the role of specific cell types in
ethanol-induced neuroimmune signaling and neuropathology. This will be achieved through cell-type specific
knockout of Toll-like Receptor (TLR)4 in astrocytes or microglia. Aim 2. Quantify ethanol-induced changes in
dynamic microglia-neuron and astrocyte-neuron interactions in vivo in the transition from normal cerebellar
development to ethanol-induced neuropathology and progression of FASD. (SubAim A) Establish whether
ethanol alters microglia interactions with dendrites and spines. (SubAim B) Determine whether ethanol alters
astrocyte signaling in response to neuronal activity and interactions with neurons. Studies in Aim 2 wi...

## Key facts

- **NIH application ID:** 9962223
- **Project number:** 5R01AA027111-03
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** Paul D Drew
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $451,350
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962223

## Citation

> US National Institutes of Health, RePORTER application 9962223, Dynamic neuroimmune interactions in the onset and progression of FASD (5R01AA027111-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9962223. Licensed CC0.

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