Prenatal alcohol and stroke susceptibility in the aging adult with FASD

项目（摘要） 胎儿酒精谱系障碍（FASD）导致终身全身性残疾，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）导致长期的 老年小鼠颅向血管功能的缺陷。PAE还减少了神经恢复， 年轻成年小鼠脑血管缺血性中风后。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，动物经历更大的中风梗塞。此外，委员会认为， 肽激素、IGF 1水平降低和IGF途径的表观遗传重编程有助于 缺血引起的脑损伤和残疾，而脑卒中后颅内IGF 1输送可改善组织 生存和行为。因此，我们假设PAE加速了大脑中年龄依赖性的增加， 通过表观遗传学编程IGF 1信号通路对缺血性中风的脆弱性”。我们计划评估 PAE对老年男性和女性成年大鼠模型脑缺血适应性的影响， 根据卒中研究指南，使用两种缺血性卒中模型，即腔内缝合闭塞模型和 内皮素-1介导的大脑中动脉血管收缩。 目的1将确定PAE影响脑损伤、感觉运动障碍和血液循环的程度。 脑屏障（BBB）通透性，在老年人缺血后。我们的假设是中间的- 与年龄匹配的对照组相比，老年PAE脑在缺血后将表现出更大的梗死体积， 与老年非PAE成人大脑相当。中年和老年PAE动物也将表现出增加的 感觉运动障碍，伴随缺血发作后BBB通透性延长 与年龄匹配的非PAE对照相比。目标2将评估PAE对衰老相关疾病的贡献。 IGF 1途径的表观遗传重编程。我们的假设是PAE在表观遗传学上 肝脏和大脑，导致成年期IGF 1的衰老相关损失。我们预计PAE会导致染色质 沉默或miRNA介导的IGF 1信号传导的抑制。目标3将决定 外源性IGF 1或肝或脑IGF 1的表观遗传刺激物对PAE成人缺血结局的影响。我们 工作假设是缺血后补充IGF 1将改善PAE对BBB的影响， 梗死体积和感觉运动功能。我们将测试PAE对 中风后用IGF 1治疗或用促进中风后损伤的药物治疗可改善中风引起的损伤。 IGF的功能，如丁酸钠，组蛋白脱乙酰酶抑制剂，和microRNA Let 7的抑制剂。 该提案检验了一个创新假设，即PAE增加了成人发病所致不良结局的风险。 疾病，在实验严格的方式。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的老年人大脑的脆弱性。调查人员有合作的历史， 为研究提供补充专业知识，为FASD成人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.