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（由申请人提供）：缺血性中风是由脑动脉血液供应中断引起的，这种中断可以是永久性的，也可以是暂时的，因为大脑对氧气和葡萄糖的需求很高且持续，血流中断会引起极端的应激反应。此外，缺血后的血液供应恢复会引起严重的炎症反应，导致额外的神经元死亡（再灌注损伤），因为缺血性中风是美国和美国的主要原因之一。在欧洲，幸存者面临着包括永久性残疾在内的衰弱后果，因此人们一直在寻求可能预防或减少缺血相关神经元死亡的治疗方法，因为大部分缺血相关神经元死亡和所有再灌注相关死亡都是在整个过程中发生的。在最初的缺血事件发生后数小时和数天内，中风后的治疗干预可能非常有益，我们和其他人已经证明，含有 BH 结构域的生存因子 Mcl-1 对于神经元的存活至关重要，特别是在某些条件下。的我们还证明，泛素连接酶 SCFFbw7 以 Mcl-1 为靶标，在神经元中进行泛素介导的蛋白水解作用，因此，RNAi 介导的该连接酶底物结合接头 Fbw7 的沉默会增加 Mcl-1 的稳态水平。因此，我们开始了一项鉴定 SCFFbw7 小分子抑制剂的计划，以开发 SCFFbw7 的小分子抑制剂。尽管缺血性脑损伤导致的细胞死亡并非导致神经元凋亡的病理状况的治疗干预。尽管细胞凋亡被认为仅是由于细胞凋亡所致，但迄今为止，我们已经鉴定出许多小分子抑制剂，它们可以阻断原代培养神经元中应激介导的细胞凋亡，其 EC50 范围为低至中皮摩尔。这些应激源包括缺氧、OGD 和炎症细胞因子治疗。一种化合物 (20aS20) 在小鼠体内的初步药代动力学分析表明，它在体内稳定，并显示出良好的 CNS 效果。因此，我们计划使用该化合物来确定靶向 SCFFbw7 是否对缺血性脑损伤小鼠模型具有治疗效果，然后证明治疗效果将证明以抑制 SCFFbw7 为中心的药物发现计划是合理的。