# C5-Circular RNA's and immune sensitization

> **NIH NIH P50** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2024 · $207,042

## Abstract

Animal and clinical studies support the biological vulnerability to chronic central nervous system (CNS) diseases
in FASD populations is driven by dysfunctional CNS-immune interactions, which include signaling and
transcriptional regulatory factors often engaged following toll-like 4 (TLR4) immune receptor activation, and may
underlie cognitive deficits precipitated by typical stressors; a secondary insult or “second hit”. Frequently, these
problems do not manifest until adolescence or early adulthood. One potential mechanism driving CNS immune
dysfunction as a consequence of prenatal alcohol exposure (PAE) (“first hit”) may involve circular RNAs
(circRNAs), which are brain-enriched non-coding RNAs capable of acting as diverse regulators of gene
expression and immune function via both transcriptional and post-transcriptional mechanisms. We recently
published that a subset of circRNAs is dysregulated in the prenatal brain as a result of PAE. Preliminary data
show dysregulated circRNAs from PAE in rodent blood and spinal cord, and sex differences were present
between elevated proinflammatory immune factors in the rodent female amygdala when stimulated by a “second
minor hit”, an acute stressor, with PAE. These immune factors overlap with the intracellular TLR4 activation
pathway thus narrowing the breadth of immune factors that may be dysregulated by PAE following a secondary
challenge. Leveraging clinical data from adolescent children with an FASD (Component 3; current Phase III
P50) who are evaluated for cognitive regulation, the goals of Component 5 is to evaluate and correlate the impact
of PAE on the expression of a subset of circRNAs, and associated mRNAs and proteins from (1) adolescent
mouse blood and brain regions that support cognitive function involving working memory following minor
challenges, and (2) saliva and blood of adolescent children with an FASD undergoing specific cognitive tasks.
The overarching hypothesis of Component 5 is that a subset of circRNAs is dysregulated by PAE, creating
brain immune sensitization that: 1) is necessary and sufficient for cognitive deficits precipitated by minor
challenges in adolescent mice, and (2) predicts cognitive deficits and stress perception in human adolescents
with FASD. Sex differences are integrated into the three Aims proposed to test this hypothesis. Component 5 of
Phase III will complement other research components by evaluating middle adolescent cognitive function of
mouse offspring with PAE using age-appropriate cognitive tests, which may predict and complement cognitive
deficits that develop in young adulthood, as assessed by other components of Phase III. CircRNA, mRNA and
protein analyses from Component-3 adolescent mice can be correlated with measured neuroimmune factors
from brains of behaviorally validated young adult mice from other components. Newly identified circRNAs that
regulate associated mRNA/protein immune factors will be correlated with Component 3’s clinical study o...

## Key facts

- **NIH application ID:** 10741691
- **Project number:** 2P50AA022534-11
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** ERIN Damita MILLIGAN
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $207,042
- **Award type:** 2
- **Project period:** 2014-08-05 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10741691

## Citation

> US National Institutes of Health, RePORTER application 10741691, C5-Circular RNA's and immune sensitization (2P50AA022534-11). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10741691. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*