Prenatal alcohol and stroke susceptibility in the aging adult with FASD

项目(摘要( 胎儿酒精谱系障碍(FASD)会导致终生系统性残疾，从而导致疾病和 FASD成人的过早死亡率。我们最近发现，产前酒精暴露(PAE)会导致长期的 衰老小鼠颅骨定向血管功能的缺陷。PAE还降低了大鼠的神经功能恢复 幼年成年小鼠脑血管缺血性卒中。初步数据显示，中年PAE 与年龄匹配的对照组或年轻的PAE成年人相比，动物经历了更大的中风梗死。此外， 多肽激素、IGF1水平的降低和IGF途径的表观遗传重新编程有助于 脑缺血导致的脑损伤和残疾，而卒中后颅内注射IGF1改善组织 生存和行为。因此，我们假设‘PAE加速了大脑中随年龄增长的增加 通过对IGF1信号通路进行表观遗传编程，对缺血性中风的易感性。我们计划评估 PAE对老龄雄性和雌性成年大鼠脑缺血适应的影响 根据卒中研究指南，使用两种模型治疗缺血性卒中：腔内缝合-闭塞和腔内闭塞 内毒素-1介导的大脑中动脉的血管收缩。 目标1将确定PAE对脑损伤、感觉运动障碍和血液的影响程度。 脑屏障(BBB)通透性，在老年人脑缺血后。我们的工作假设是，中间- 与年龄匹配的对照组相比，老年PAE脑缺血后显示出更大的脑梗塞体积，并且 与老年非PAE成人脑相当。中老年PAE动物也将表现出增加 感觉运动障碍，伴有脑缺血后血脑屏障通透性延长 与年龄匹配的非PAE对照组相比。目标2将评估PAE对衰老相关的贡献 IGF1途径的表观遗传重编程。我们的工作假设是PAE在表观上重新编程 肝脏和大脑导致成年后与衰老相关的IGF1丢失。我们预计PAE将导致染色质 沉默或miRNA介导的IGF1信号的翻译抑制。目标3将确定 外源性IGF1或肝脏或脑IGF1的表观遗传刺激因子对成人PAE缺血结局的影响。我们的 工作假说是缺血后补充IGF1将改善PAE对血脑屏障的影响， 老年动物的脑梗塞体积和感觉运动功能。我们将测试PAE在多大程度上影响 卒中后应用IGF1或促进剂可改善卒中所致的损害 IGF的功能，如丁酸钠，一种组蛋白去乙酰化酶抑制剂，以及microRNA Let7的对抗剂。 这项建议测试了一项创新的假设，即PAE会增加成人发病的不良后果的风险 疾病，以一种实验严谨的方式。它意义重大，因为它解决了一个关键的知识差距 关于患有FASD的老年成年人的大脑脆弱性。调查人员有合作的历史，而且 将补充专业知识引入研究，为成人FASD的临床护理提供信息。

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.