Prenatal Alcohol and Stroke Susceptibility in the Aging Adult with FASD
Project(Summary(Fetal Alcohol Spectrum Disorders (FASD) result in life-long systemic disabilities that contribute to disease andpremature mortality in FASD adults. We recently found that prenatal alcohol-exposure (PAE) led to long-termdeficits in cranially-directed vascular function in aging mice. PAE also diminished neurological recovery inyoung adult mice following cerebrovascular ischemic stroke. Preliminary data indicate that middle-aged PAEanimals 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 toischemia-induced brain damage and disability, while intracranial IGF1 delivery after stroke improves tissuesurvival and behavior. Therefore, we hypothesize that â€˜PAE accelerates the age-dependent increase in brainvulnerability to ischemic stroke by epigenetically programming IGF1 signaling pathwaysâ€™â€™. We plan to assesseffects of PAE on brain adaptation to ischemia in aging male and female adults in rat models, and consistentwith stroke research guidelines, use two models for ischemic stroke by intraluminal suture-occlusion and byendtothelin-1-mediated vasoconstriction of the middle cerebral artery.Aim 1 will determine the extent to which PAE influences brain damage, sensorimotor impairment, and bloodbrain 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, andcomparable to the aged non-PAE adult brain. Middle-aged and aged PAE animals will also exhibit increasedsensorimotor impairment, accompanied by prolonged BBB permeability following an ischemic episodecompared to age-matched, non-PAE controls. Aim 2 will assess the contribution of PAE to aging-relatedepigenetic reprogramming of IGF1 pathways. Our working hypothesis is that PAE epigenetically reprogramsliver and brain resulting in aging-related loss of IGF1 in adulthood. We expect that PAE will result in chromatinsilencing or miRNA-mediated translation-repression of IGF1 signaling. Aim 3 will determine the impact ofexogenous IGF1, or epigenetic stimulators of hepatic or brain IGF1, on ischemia outcomes in PAE adults. Ourworking 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 onstroke-induced impairment are ameliorated by post-stroke treatment with IGF1, or with agents that promoteIGF 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-onsetdisease, in an experimentally rigorous way. It is significant because it addresses a critical knowledge gapabout brain vulnerability in aging adults with FASD. The investigators have a history of collaboration, andbring complementary expertise to studies that will inform clinical care of adults with FASD.