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（概要（ 胎儿酒精谱系障碍 (FASD) 会导致终生全身性残疾，从而导致疾病和 我们最近发现产前酒精暴露 (PAE) 会导致长期的 FASD 成人过早死亡。 PAE 的颅脑血管功能缺陷也削弱了神经功能的恢复。 脑血管缺血性中风后的年轻成年小鼠的初步数据表明中年 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。 肽激素 IGF1 水平的降低和 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，而中风后颅内 IGF1 输送可改善组织 因此，我们发现“PAE 会加速大脑的年龄依赖性增长”。 通过表观遗传编程 IGF1 信号通路来评估缺血性中风的脆弱性”。 PAE 对大鼠模型中老年雄性和雌性成年大脑缺血适应的影响，并且一致 根据中风研究指南，使用两种缺血性中风模型：腔内缝合闭塞和 内皮素-1介导的大脑中动脉血管收缩。 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，在成人缺血后衰老。 与年龄匹配的对照组相比，老年 PAE 大脑在缺血后会表现出更大的梗塞体积，并且 与老年非 PAE 成年动物相比，中年和老年 PAE 动物也会表现出增加。 感觉运动障碍，伴有缺血发作后血脑屏障通透性延长 与年龄匹配的非 PAE 对照相比，目标 2 将评估 PAE 对衰老相关的影响。 IGF1 途径的表观遗传重编程我们的工作假设是 PAE 进行表观遗传重编程。 肝脏和大脑会导致成年后与衰老相关的 IGF1 损失，我们预计 PAE 会导致染色质减少。 沉默或 miRNA 介导的 IGF1 信号翻译抑制将决定 Aim 3 的影响。 外源性 IGF1 或肝脏或大脑 IGF1 的表观遗传刺激物对 PAE 成人缺血结果的影响。 工作假设是缺血后补充 IGF1 将改善 PAE 对 BBB 的影响， 我们将测试 PAE 对衰老动物的梗塞体积和感觉运动功能的影响程度。 中风后使用 IGF1 或促进药物治疗可改善中风引起的损伤 IGF 功能，如丁酸钠、组蛋白脱乙酰酶抑制剂和 microRNA Let7 的拮抗剂。 该提案测试了一个创新假设，即 PAE 会增加成人发病导致不良后果的风险 以严格实验的方式研究疾病，这一点很重要，因为它解决了一个关键的知识空白。 关于患有 FASD 的老年人的大脑脆弱性 研究人员有合作历史，并且 补充专业知识的研究将为 FASD 成人的临床护理提供信息。

项目成果

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

产前酒精引起成年大鼠免疫、代谢和神经行为结果的性别差异。

• 发表时间: 2021
• 作者: Bake, Shameena;Pinson, Marisa R;Pandey, Sivani;Chambers, Joanna P;Mota, Roxanna;Fairchild, Ashlyn E;Miranda, Rajesh C;Sohrabji, Farida
• 通讯作者: Sohrabji, Farida

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

产前接触酒精会加剧急性感觉运动缺陷，并阻碍成人脑血管缺血性中风影响的长期行为恢复。

• 发表时间: 2022-12
• 作者: Bake, Shameena;Hurst, David A;Miranda, Rajesh C;Sohrabji, Farida
• 通讯作者: Sohrabji, Farida

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

产前酒精改变成人发病的脑血管缺血性中风后肠门组织的炎症特征。

• 发表时间: 2023-10-20
• 影响因子: 5.8
• 作者: Pinson, Marisa R;Bake, Shameena;Hurst, David A;Samiya, Nadia T;Sohrabji, Farida;Miranda, Rajesh C
• 通讯作者: Miranda, Rajesh C