Fbw7 as a therapeutic target for treating ischemic brain injury

Fbw7作为治疗缺血性脑损伤的治疗靶点

基本信息

批准号：
9063625
负责人：
Steven I Reed
金额：
$ 37.68万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-15 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9063625
关键词：
Apoptosis Apoptotic Behavior assessment Binding Blood flow Brain Cause of Death Cell Death Cessation of life Dose Drug Kinetics Environment Europe Event Glucose Goals Harvest Health Hour Hypoxia Infarction Inflammatory Inflammatory Response Interruption Ischemia Ischemic Brain Injury Ischemic Stroke Ligase Mediating Middle Cerebral Artery Occlusion Modeling Mus Neurons Oxygen Patients Penetrance RNA Interference Recovery of Function Reperfusion Injury Reperfusion Therapy Sampling Stress Stroke Survivors Testing Therapeutic Intervention Time Treatment Efficacy Ubiquitin-mediated Proteolysis Pathway United States Vascular blood supply Western Blotting biological adaptation to stress cytokine disability drug discovery effective therapy in vivo inhibitor/antagonist mouse model neuron apoptosis neuron loss neuronal survival prevent programs research study response restoration small molecule small molecule inhibitor stressor therapeutic target ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): Ischemic stroke results from interruption of brain arterial blood supply. The interruption can be permanent or transient. Since the requirements for oxygen and glucose in the brain are high and constant, interruption of blood flow induces extreme stress responses, leading ultimately to neuronal death. In addition, restoration of blood supply subsequent to ischemia induces a profound inflammatory response causing additional neuronal death (reperfusion injury). As ischemic stroke is one of the leading causes of death in both the United States and Europe, and survivors are faced with debilitating consequences, including permanent disability, therapies that might prevent or reduce ischemia-related neuronal death have been sought. Since much of the ischemia-related neuronal death and all of the reperfusion-related death occurs over the course of hours and days following the initial ischemic event, therapeutic intervention subsequent to a stroke has the potential to be highly beneficial. We and others have demonstrated that BH domain-containing survival factor, Mcl-1, is critical for neuronal survival, particularly under conditions of stress. We have also demonstrated that a ubiquitin ligase, SCFFbw7 targets Mcl-1 for ubiquitin-mediated proteolysis in neurons. Accordingly, RNAi- mediated silencing of the substrate-binding adaptor of this ligase, Fbw7, increases steady state levels of Mcl-1 in primary neuronal cultures and protects them from stress-associated apoptosis. We have therefore embarked on a program to identify small molecule inhibitors of SCFFbw7 in order to develop therapeutic interventions for pathological conditions resulting in neuronal apoptosis. Although cell death due to ischemic brain injury is not considered to be due solely to apoptosis, apoptotic neuronal death is thought to be a significant factor. To date we have identified a number of small molecule inhibitors that block stress-mediated apoptosis in primary cultured neurons with EC50s in the low- to mid-picomolar range. These stressors include hypoxia, OGD, and treatment with inflammatory cytokines. Preliminary pharmacokinetic analysis in the mouse of one compound (20aS20) indicates that it is stable in vivo and shows good CNS penetrance. Therefore, we plan to use this compound to determine if targeting SCFFbw7 has therapeutic efficacy in mouse models of ischemic brain injury. Demonstrating therapeutic efficacy would then justify a drug discovery program centered on inhibition of SCFFbw7.

描述（适用提供）：缺血性中风是由脑动脉血液供应中断引起的。中断可以是永久的或瞬态的。由于大脑中氧气和葡萄糖的需求高且恒定，因此血流的中断会引起极端的压力反应，最终导致神经元死亡。此外，缺血后的血液供应的恢复会引起深刻的炎症反应，导致额外的神经元死亡（再灌注损伤）。正如缺血性中风是美国和欧洲的主要死亡原因之一，生存面临着令人衰弱的后果，包括永久残疾，可能预防或减少缺血相关的神经元死亡的疗法。由于与缺血相关的神经元死亡和所有与再灌注有关的死亡发生在初次缺血事件后的几个小时和几天内，因此。中风后的干预有可能是高度有益的。我们和其他人已经证明，含BH结构域的生存因子MCL-1对于神经元生存至关重要，特别是在压力条件下。我们还证明了泛素连接酶SCFFBW7靶向MCL-1用于神经元中泛素介导的蛋白水解。根据该连接酶FBW7的底物结合适配器的RNAi介导的沉默，增加了原发性神经元培养物中MCL-1的稳态水平，并保护它们免受与压力相关的细胞凋亡。因此，我们开始了一个程序，以鉴定SCFFFBW7的小分子抑制剂，以开发有关病理状况的治疗干预措施，从而导致神经元细胞凋亡。尽管缺血性脑损伤导致的细胞死亡不是被认为仅是由于凋亡，凋亡神经元死亡被认为是一个重要因素。迄今为止，我们已经确定了许多小分子抑制剂，这些抑制剂阻断了应力介导的原代培养神经元中EC50的凋亡，在低至中摩尔范围内。这些压力源包括缺氧，OGD和炎症细胞因子治疗。一种化合物的小鼠（20AS20）中的初步药代动力学分析表明它在体内是稳定的，并且显示出良好的中枢神经系统渗透率。因此，我们计划使用该化合物来确定靶向SCFFFBW7在缺血性脑损伤的小鼠模型中是否具有治疗效率。然后证明治疗效率将证明以抑制SCFFBW7为中心的药物发现计划合理。