Therapeutic Targeting of an lncRNA in Experimental Stroke Using STAIR Criteria

哺乳动物基因组编码数万个长的非编码RNA(LncRNAs)，这些RNA是 成为转录和翻译的重要调节者。能级中的任何扰动 而lncRNAs的功能可望促进病变的发生。我们最近展示了 成年啮齿动物短暂性局灶性脑缺血(卒中)迅速改变大脑 LncRNAs的表达谱。我们进一步表明，缺血后的脑损伤和 通过抑制一种名为FosDT的lncRNA，可以显著缓解神经功能障碍 被观察到是在中风后诱发的。由于它们作为表观遗传学的功能重要性 转录调节因子，lncRNAs有巨大的潜力被开发为中风 治疗。因此，我们目前建议测试抑制FosDT在啮齿动物中风中的有效性 模特们。我们推测FosDT是一种新的保护脑损伤的治疗靶点 中风。“据我们所知，这是第一次全面测试 IncRNA在保护中风后的大脑中的作用。最近的指南建议中风治疗 发育应遵循阶梯建议的标准(中风治疗学术 行业圆桌会议)财团。因此，我们将把其中许多建议纳入 目前的FosDT治疗试验。目标1是测试以下情况下的剂量和机会窗口 卒中的FosDT治疗与性别和年龄有关。目标2是测试中风后的FosDT治疗 作为缺血类型、给药途径和全身毒性的函数。AIM 3将评估 缺血后FosDT治疗的疗效与物种和糖尿病(并存)有关 情况)，并确定该疗法是否影响缺血后的病理生理 机械装置。目标4将评估FosDT上游和下游的机制 在缺血的大脑中。总体而言，这是第一项系统研究，以测试治疗潜力 靶向lncRNA以保护中风后的大脑。

Mammalian genome encodes tens of thousands of long noncoding RNAs (lncRNAs) which are emerging as important regulators of transcription and translation. Any perturbation in the levels and function of lncRNAs can be expected to promote pathological changes. We recently showed that transient focal cerebral ischemia (stroke) in adult rodents rapidly changes the cerebral expression profiles of lncRNAs. We further show that post-ischemic brain damage and neurological dysfunction can be mitigated significantly by inhibiting an lncRNA called FosDT that was observed to be induced after stroke. Due to their functional importance as epigenetic modulators of transcription, lncRNAs has a tremendous potential to be developed as stroke therapies. Hence, we currently propose testing the efficacy of inhibiting FosDT in rodent stroke models. We hypothesize that “FosDT is a novel therapeutic target to protect brain after stroke.” This is the first study to our knowledge to comprehensively test the significance of an lncRNA in protecting the brain after stroke. Recent guidelines suggest that stroke therapeutic development should follow the criteria suggested by the STAIR (Stroke Treatment Academic Industry Roundtable) consortium. Hence, we will incorporate many of those recommendations in the present FosDT therapeutic testing. Aim 1 is to test the dose and window of opportunity after stroke for FosDT therapy as a function of sex and age. Aim 2 is to test post-stroke FosDT therapy as a function of type of ischemia, route of administration, and systemic toxicity. Aim 3 will evaluate the efficacy of post-ischemic FosDT therapy as a function of species and diabetes (a comorbid condition) and to identify if this therapy influences the post-ischemic pathophysiologic mechanisms. Aim 4 will evaluate the mechanisms that are upstream and downstream of FosDT in ischemic brain. Overall, this is the first systematic study to test the therapeutic potential of targeting an lncRNA to protect brain after stroke.