# Mechanisms of Glucocorticoid Resistance in Prenatal Alcohol Exposure

> **NIH NIH P50** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2020 · $266,525

## Abstract

Project Summary
Many of the physiological processes affected by prenatal alcohol exposure (PAE) are regulated by
glucocorticoids (GCs). GC resistance (i.e., reduced sensitivity to the actions of GCs), which may result from
aberrant in utero glucocorticoid programming, is associated with both a variety of chronic diseases, many of
which are immune function related, and PAE. Our goal is to identify molecular mechanisms of alcohol-mediated
alterations in the programming of glucocorticoid sensitivity in the developing fetus, and to track these changes
into adulthood. We will use this information to develop targeted interventions that reverse or reduce the effects
of PAE on GC sensitivity and consequent responses of immune signaling molecules. This proposal will test the
hypothesis that PAE modifies the long noncoding RNA, Growth arrest-specific 5 (Gas5), which acts as a
glucocorticoid receptor (GR) decoy to regulate GR-mediated gene expression.
Our hypotheses are two-fold: 1.) PAE produces glucocorticoid resistance that is expressed as: a.)
dysregulation of the hypothalamic pituitary (HPA) axis and an increase in pro-inflammatory to anti-inflammatory
cytokine ratio under stressful conditions, b.) a critical developmental shift in the normal stress and immune
hyporesponsive early postnatal periods and c.) a decrease in the GRα/GRβ ratio. 2.) This maladaptive
glucocorticoid resistance is programmed in the fetal brain as a result of an elevation in fetal brain Gas5 and
maintained in adulthood by increases in FK506-bindinig protein-51 (FKBP51) levels.
We will test these hypotheses using our established mouse model of PAE and three specific study designs:
Aim 1.) PAE produces a measurable increase in glucocorticoid resistance: We will confirm physiologically
relevant GC resistance in adult male and female PAE and saccharin (SAC) control mice by assessing HPA
responding, pro- and anti-inflammatory cytokine/chemokine protein levels and levels of specific GR-regulated
gene transcripts (including cytokines/chemokines) in response to stress activation. GC resistance will also be
assessed by the ratio of GRα/GRβ, as well as measures of the levels of FKPB5 methylation.
Aim 2.) PAE affects the developmental programming of GC responding: We will determine the impact of
PAE on both the immune and stress hyporesponsive periods using maternal separation. HPA axis
responsiveness, levels of frontal cortical cytokines/chemokines, FKBP51 protein and Gas5 RNA expression and
their associations with GR will be determined. We will also measure the relative expression of GR isoforms GRα
and GRβ.
Aim 3.) Inhibition or reduction of prenatal Gas5 should restore normal GC sensitivity in the PAE mice.
Delivery of an LNA-oligonucleotide target site blocker directed at the GRE binding region of Gas-5 or shRNA
mediated gas5 knockdown during the embryonic period will restore normal GC responding and sensitivity
(inclusive of stress responses, immune signaling molecules and nuclear GR-...

## Key facts

- **NIH application ID:** 9980241
- **Project number:** 5P50AA022534-07
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** ANDREA M ALLAN
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $266,525
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980241

## Citation

> US National Institutes of Health, RePORTER application 9980241, Mechanisms of Glucocorticoid Resistance in Prenatal Alcohol Exposure (5P50AA022534-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9980241. Licensed CC0.

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