FOXOs in ischemic stroke

项目摘要 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发展 病理学和痴呆症为了对抗I/R诱导的病理性级联反应，许多神经保护剂 策略和试剂已经被确定和研究。然而，这些神经保护的翻译 策略和试剂的临床试验一直不成功，迄今为止，组织纤溶酶原激活剂， 仍然是FDA批准的唯一用于治疗缺血性中风的药物。因此，有义务查明和 验证I/R引起的脑部疾病的其他治疗靶点和试剂。本项目的目标 是为了验证一个新的治疗靶点，FOXO 4，因为以前的数据表明，FOXO 4促进早期 组织炎症和FOXO 4的下调与细胞死亡减少和细胞凋亡增加有关。 缺血外周组织中的新生血管。重要的是，我们的试验数据表明，敲除（KO） FOXO 4基因显著减弱I/R引起的脑损伤，并改变了与AD相关的许多基因。 缺血性中风小鼠模型。基于这些观察，我们假设选择性抑制 FOXO 4活性对缺血性卒中引起的脑损伤和AD样病理具有保护作用。测试 假设，我们将（1）确定FOXO 4在缺血性卒中诱导的脑损伤中的作用， 改良小鼠，（2）研究鉴定的FOXO 4抑制剂在治疗缺血性中风引起的脑损伤中的作用， 了解缺血性卒中后FOXO 4的缺失如何提供神经保护。

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.