FOXOs in ischemic stroke

项目总结 脑缺血再灌注(I/R)与神经炎症、线粒体功能障碍和 氧化应激导致脑损伤、功能障碍和阿尔茨海默病样症的发展 病理学和痴呆症。对抗I/R引起的病理性级联反应，众多神经保护 已经确定并研究了策略和试剂。然而，这些神经保护的翻译 临床试验的策略和试剂一直没有成功，到目前为止，组织纤溶酶原激活剂 仍然是FDA批准的唯一治疗缺血性中风的药物。因此，有义务确定和 验证I/R引起的脑部疾病的其他治疗靶点和试剂。这个项目的目标是 是验证一种新的治疗靶点FOXO4，因为之前的数据表明FOXO4促进早期 组织炎症和FOXO4下调与细胞死亡减少和增加有关 缺血周围组织中的新生血管。重要的是，我们的试点数据显示， FOXO4基因显著减轻脑I/R损伤并改变AD相关基因 缺血性卒中小鼠模型。基于这些观察，我们假设选择性抑制 FOXO4活性对缺血性中风引起的脑损伤和AD样病理具有保护作用。要测试 假设，我们将(1)确定FOXO4在缺血性卒中所致脑损伤中的作用 改良小鼠，(2)研究已鉴定的FOXO4抑制剂在治疗缺血性中风引起的脑损伤中的作用， 以及(3)了解丧失FOXO4是如何在缺血性中风后提供神经保护的。

PROJECT SUMMARY Cerebral ischemia-reperfusion (I/R) is associated with neuroinflammation, mitochondrial dysfunction and oxidative stress, leading to brain injury, function disability and development of Alzheimer’s disease-like pathology and dementia. To fight against I/R induced pathological cascades, numerous neuroprotective strategies and reagents have been identified and studied. However, translation of these neuroprotective strategies and reagents to clinical trials has been unsuccessful, and to date, the tissue plasminogen activator remains to be the only FDA approved drug for treating ischemic stroke. Thus, it is obligatory to identify and validate additional therapeutic targets and reagents for I/R-caused brain disorder. The objective of this project is to validate a novel therapeutic target, FOXO4, as previous data have shown that FOXO4 promotes early tissue inflammation, and downregulation of FOXO4 is associated with reduced cell death and increased neovasculature in ischemic peripheral tissues. Importantly, our pilot data have shown that knockout (KO) of FOXO4 gene dramatically attenuates I/R-caused brain injury and alters numerous genes linked to AD in an ischemic stroke mouse model. Based on these observations, we hypothesize that selective inhibition of FOXO4 activity is protective against ischemic stroke-caused brain injury and AD-like pathology. To test the hypothesis, we will (1) determine the role of FOXO4 in ischemic stroke-induced brain injury using genetically modified mice, (2) study the role of identified FOXO4 inhibitors in treating ischemic stroke-caused brain injury, and (3) understand how loss of FOXO4 confers neuroprotection following ischemic stroke.