Identifying activators of interferon regulatory factors for neuroprotection.

摘要 中风是美国发病率和死亡率的主要原因。但只有不到10%的患者 有资格接受目前批准的组织纤溶酶原激活剂或血栓切除术干预。我们寻求 开发新的治疗方法，以减少缺血性脑损伤和功能障碍的程度， 脑损伤，这是一个严重未满足医疗需求的领域。我们发现干扰素调节因子 (IRF)介导的基因转录可能代表一种内源性神经保护机制， 与缺血性损伤的减少有关。使用中风的细胞和小鼠模型， 证明了在缺血性损伤后施用已知诱导IRF的化合物 介导的基因转录，显著降低损伤程度。这些结果表明，激活 脑卒中后IRF转录因子的表达可能是治疗脑卒中的一种可行的治疗干预措施 患者这个STTR项目的最终目标是鉴定在两种细胞中诱导IRF转录的化合物， 小鼠和人细胞，但具有最小的脱靶免疫活性。我们将鉴定化合物， 可接受的目标质量标准，通过命中铅协议优化这些化合物，并最终测试 在脑缺血性损伤小鼠模型中的功效。 我们提出以下目标： 目的1：鉴定用于使用神经保护剂的急性神经保护剂的治疗开发的先导化合物。 实验验证的高通量筛选平台。 目标2：通过对先导化合物的描述，对先导化合物进行评价和排序。 目的3：评价先导化合物的PK和耐受性，并确定在小鼠模型中的功效。 脑缺血损伤

Abstract Stroke is a leading cause of morbidity and mortality in the United States. However less than 10% of patients are eligible for the current approved interventions of tissue plasminogen activator or thrombectomy. We seek to develop new therapeutics to reduce the extent of damage and functional impairment resulting from ischemic injury to the brain, an area of significant unmet medical need. We have found that interferon regulatory factor (IRF) mediated gene transcription may represent an endogenous mechanism of neuroprotection that is associated with a reduction in ischemic injury. Using both cell and mouse models of stroke we have demonstrated that administration of compounds following the ischemic insult, that are known to induce IRF mediated gene transcription, significantly reduces the extent of damage. These results indicate that activation of IRF transcription factors following stroke may be a viable therapeutic intervention for the treatment of stroke patients. The ultimate goal of this STTR program is to identify compounds that induce IRF transcription in both mouse and human cells but with minimal off-target immune activity. We will identify compounds with acceptable target specification, optimize these compounds through hit to lead protocols and ultimately test for efficacy in a mouse model of cerebral ischemic injury. We propose the following aims: Aim 1: Identify lead compounds for therapeutic development of an acute neuroprotectant using an experimentally validated high throughput screening platform. Aim 2: Evaluate and rank lead compounds through hit to lead characterization. Aim 3: Evaluate PK and tolerability of lead compounds and determine efficacy in a mouse model of cerebral ischemic injury.