Studies of the Therapeutic Role of IU1 in a Mouse Model of Ischemic Stroke

IU1 在缺血性中风小鼠模型中的治疗作用研究

• 批准号: 8773223
• 负责人: Hongmin Wang
• 金额: $ 6.98万
• 依托单位: UNIVERSITY OF SOUTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8773223
• 关键词: Acute; Alteplase; Animal Behavior; Animal Model; Attenuated; Blood - brain barrier anatomy; Brain; Cell Culture Techniques; Cell Death; Cells; Cerebral Ischemia; Cerebrum; Cessation of life; Data; Deubiquitinating Enzyme; Disease; Dose; Employee Strikes; Enzymes; Event; Excision; FDA approved; Forelimb; Green Fluorescent Proteins; Health; Infarction; Intraperitoneal Injections; Ischemia; Ischemic Stroke; Length; Link; Maximum Tolerated Dose; Modeling; Mus; Nature; Nerve Cell Survival; Neurologic Deficit; Neuronal Dysfunction; Neuronal Injury; Neurons; Outcome; Oxidative Stress; Peripheral; Pharmaceutical Preparations; Physiological; Play; Process; Production; Proteins; Public Health; Reagent; Recovery of Function; Reperfusion Therapy; Reporter; Resistance; Role; Rotarod Performance Test; Saline; Signal Transduction; Stroke; System; Testing; Therapeutic; Therapeutic Studies; Transgenic Mice; Ubiquitin; Ubiquitination; United States; Walking; Work; design; disability; effective therapy; improved; inhibitor/antagonist; mortality; mouse model; multicatalytic endopeptidase complex; novel therapeutics; protein aggregate; protein degradation; public health relevance; repaired; research study; screening; small molecule; sound

DESCRIPTION (provided by applicant): Stroke is a leading cause of high mortality and long-term disability in the United States. Stroke is associated with the over-production of misfolded/aggregating proteins. However, the role of aberrant protein clearance on the outcome of ischemic stroke remains far from being understood. The ubiquitin proteasome system (UPS) plays a critical role in the removal of abnormal proteins. The UPS is regulated by a number of factors but recent data indicate that the proteasome-associated deubiquitinating enzymes (DUBs) play an important role in regulating proteasome activity. USP14 is the DUB that is reversibly associated with the proteasome and modulates proteasome activity. Recently, a USP14-specific small molecule inhibitor, IU1, was identified (Lee et al. 2010, Nature 467:179-184). In cell culture, IU1 accelerates the clearance of oxidized proteins and imparts a resistance effect on oxidative stress-induced cell death. These results suggest that IU1 may be a potential drug that can be used for treating cerebral ischemia/reperfusion-caused disorders. However, this has not been tested in ischemic stroke animal models. In this project, we hypothesize that peripheral administration of IU1 in mice will attenuate neuronal death and promote structural repair and functional recovery following transient cerebral ischemic stroke. To test this hypothesis, the following specific aims will be pursued. 1. Examine whether IU1, a DUB inhibitor, enhances the degradation of a surrogate proteasome substrate in a proteasome function reporter mouse model with or without ischemia/reperfusion. 2. Determine whether peripheral administration of IU1 protects neurons from transient focal cerebral ischemia-caused neuronal injury.

描述（由申请人提供）：中风是美国高死亡率和长期残疾的主要原因。中风与错误折叠/聚集蛋白的过度产生有关。然而，异常蛋白质清除对缺血性卒中结局的作用仍远未被理解。泛素蛋白酶体系统（UPS）在去除异常蛋白质中起着关键作用。UPS受许多因素的调节，但最近的数据表明，蛋白酶体相关的去泛素化酶（DUBs）在调节蛋白酶体活性中起着重要作用。USP 14是与蛋白酶体可逆结合并调节蛋白酶体活性的DUB。最近，鉴定了USP 14特异性小分子抑制剂IU 1（Lee等人，2010，Nature 467：179-184）。在细胞培养中，IU 1加速氧化蛋白的清除，并对氧化应激诱导的细胞死亡产生抵抗作用。这些结果表明，IU 1可能是一种潜在的药物，可用于治疗脑缺血/再灌注引起的疾病。然而，这尚未在缺血性中风动物模型中进行测试。在这个项目中，我们假设IU 1在小鼠外周给药将减弱短暂性脑缺血性卒中后神经元死亡，促进结构修复和功能恢复。为了检验这一假设，将追求以下具体目标。1.检查IU 1（DUB抑制剂）是否在有或无缺血/再灌注的蛋白酶体功能报告小鼠模型中增强替代蛋白酶体底物的降解。2.确定外周给予IU 1是否保护神经元免受短暂局灶性脑缺血引起的神经元损伤。