# Prenatal alcohol and stroke susceptibility in the aging adult with FASD

> **NIH NIH R01** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2021 · $334,125

## Abstract

Project(Summary(
Fetal Alcohol Spectrum Disorders (FASD) result in life-long systemic disabilities that contribute to disease and
premature mortality in FASD adults. We recently found that prenatal alcohol-exposure (PAE) led to long-term
deficits in cranially-directed vascular function in aging mice. PAE also diminished neurological recovery in
young adult mice following cerebrovascular ischemic stroke. Preliminary data indicate that middle-aged PAE
animals experience larger stroke infarcts compared to age-matched controls or young PAE adults. Moreover,
reduced levels of the peptide hormone, IGF1, and epigenetic re-programming of IGF pathways contribute to
ischemia-induced brain damage and disability, while intracranial IGF1 delivery after stroke improves tissue
survival and behavior. Therefore, we hypothesize that ‘PAE accelerates the age-dependent increase in brain
vulnerability to ischemic stroke by epigenetically programming IGF1 signaling pathways’’. We plan to assess
effects of PAE on brain adaptation to ischemia in aging male and female adults in rat models, and consistent
with stroke research guidelines, use two models for ischemic stroke by intraluminal suture-occlusion and by
endtothelin-1-mediated vasoconstriction of the middle cerebral artery.
Aim 1 will determine the extent to which PAE influences brain damage, sensorimotor impairment, and blood
brain barrier (BBB) permeability, in aging adults following ischemia. Our working hypothesis is that the middle-
aged PAE brain will exhibit a larger infarct volume following ischemia, compared to age-matched controls, and
comparable to the aged non-PAE adult brain. Middle-aged and aged PAE animals will also exhibit increased
sensorimotor impairment, accompanied by prolonged BBB permeability following an ischemic episode
compared to age-matched, non-PAE controls. Aim 2 will assess the contribution of PAE to aging-related
epigenetic reprogramming of IGF1 pathways. Our working hypothesis is that PAE epigenetically reprograms
liver and brain resulting in aging-related loss of IGF1 in adulthood. We expect that PAE will result in chromatin
silencing or miRNA-mediated translation-repression of IGF1 signaling. Aim 3 will determine the impact of
exogenous IGF1, or epigenetic stimulators of hepatic or brain IGF1, on ischemia outcomes in PAE adults. Our
working hypothesis is that IGF1 supplementation after ischemia will ameliorate effects of PAE on the BBB,
infarct volume, and sensorimotor function in aging animals. We will test the extent to which effects of PAE on
stroke-induced impairment are ameliorated by post-stroke treatment with IGF1, or with agents that promote
IGF function, like sodium butyrate, a histone deacetylase inhibitor, and an antagomir to the microRNA Let7.
This proposal tests an innovative hypothesis that PAE increases risk for adverse outcomes due to adult-onset
disease, in an experimentally rigorous way. It is significant because it addresses a critical knowledge gap
about brain v...

## Key facts

- **NIH application ID:** 10172800
- **Project number:** 5R01AA026756-04
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **Principal Investigator:** Rajesh C Miranda
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $334,125
- **Award type:** 5
- **Project period:** 2018-07-02 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10172800

## Citation

> US National Institutes of Health, RePORTER application 10172800, Prenatal alcohol and stroke susceptibility in the aging adult with FASD (5R01AA026756-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10172800. Licensed CC0.

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