Prenatal alcohol and stroke susceptibility in the aging adult with FASD

患有 FASD 的老年人的产前酒精和中风易感性

• 批准号: 10396634
• 负责人: Rajesh C Miranda
• 金额: $ 33.41万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-02 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396634
• 关键词: Accidents; Acute; Address; Adult; Affect; Age; Aging; Alcohol abuse; Alcoholism; Alcohols; Animal Model; Animals; Behavior; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Injuries; Cardiovascular Diseases; Cardiovascular system; Caring; Cephalic; Chromatin; Collaborations; Data; Disease; Disease Outcome; Epigenetic Process; Exhibits; Female; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal alcohol effects; First Pregnancy Trimester; Goals; Guidelines; HDAC4 gene; Health; Heart Hypertrophy; Hepatic; Histone Deacetylase Inhibitor; Hypertension; IGF1 gene; Impairment; Individual; Industry; Infarction; Inflammation; Institutes; Ischemia; Ischemic Stroke; Kidney Failure; Knowledge; Life; Liver; Longevity; Mediating; Mental Health; Metabolic Diseases; MicroRNAs; Middle Cerebral Artery Occlusion; Mission; Modeling; Mus; Onset of illness; Outcome; Outcome Study; Pathway interactions; Phase; Predisposition; Premature Mortality; Publishing; Rattus; Recording of previous events; Recovery; Repression; Research; Research Personnel; Risk; Risk Factors; Sensorimotor functions; Signal Pathway; Signal Transduction; Sodium Butyrate; Somatomedins; Stroke; Supplementation; Surgical sutures; Teenagers; Testing; Tissue Survival; Translations; adverse outcome; age related; aged; alcohol exposure; alcohol prevention; alcohol related consequences; base; blood-brain barrier permeabilization; cerebrovascular; clinical care; disability; experience; hypertensive; hypoperfusion; improved; innovation; male; middle age; middle cerebral artery; mouse model; neurological recovery; peptide hormone; post stroke; prenatal; stroke incidence; stroke outcome; stroke therapy; vasoconstriction; virtual; young adult

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 vulnerability in aging adults with FASD. The investigators have a history of collaboration, and bring complementary expertise to studies that will inform clinical care of adults with FASD.

项目总结(

项目成果

Prenatal alcohol alters inflammatory signatures in enteric portal tissues following adult-onset cerebrovascular ischemic stroke.

• DOI: 10.1016/j.isci.2023.107920
• 发表时间: 2023-10-20
• 期刊: iScience
• 影响因子: 5.8
• 作者: Pinson MR;Bake S;Hurst DA;Samiya NT;Sohrabji F;Miranda RC
• 通讯作者: Miranda RC

Prenatal alcohol-induced sex differences in immune, metabolic and neurobehavioral outcomes in adult rats.

• DOI: 10.1016/j.bbi.2021.08.207
• 发表时间: 2021-11
• 期刊: Brain, behavior, and immunity
• 作者: Bake S;Pinson MR;Pandey S;Chambers JP;Mota R;Fairchild AE;Miranda RC;Sohrabji F
• 通讯作者: Sohrabji F

Prenatal alcohol exposure exacerbates acute sensorimotor deficits and impedes long-term behavioral recovery from the effects of an adult-onset cerebrovascular ischemic stroke.

• DOI: 10.1111/acer.14952
• 发表时间: 2022-12
• 期刊: Alcoholism, clinical and experimental research