Role of ubiquilin in ischemic stroke

 描述(申请人提供)：在美国，中风是导致高死亡率和长期残疾的主要原因。中风与活性氧和氮的过量产生有关，这会导致蛋白质的错误折叠和聚集。然而，蛋白清除异常在缺血性卒中预后中的作用仍远未被了解。泛素(Ubqln)是一种泛素样蛋白，可抑制缺氧、营养饥饿素和蛋白质错误折叠诱导的细胞死亡。为了了解Ubqln在缺血性卒中后神经元修复中的作用，我们最近建立了Ubqln转基因和条件性基因敲除的小鼠模型，并在动物身上发现，Ubqln的过度表达可以保护神经元免受氧化应激和缺血引起的脑损伤，而该基因的敲除则加剧了脑缺血引起的神经元损伤，并延迟了功能的恢复。尽管这些观察证实了Ubqln是一个治疗靶点，但转基因操作导致的Ubqln过度表达发生在缺血性卒中事件之前，目前尚不清楚延迟的Ubqln在缺血后脑中的过度表达是否仍然有益。在这个修订的方案中，我们假设在缺血性卒中后一个临床相关的时间窗口内，Ubqln的延迟升高可以减少神经元损伤，促进动物功能恢复。为了验证这一假说，将寻求以下具体目标：(1)确定Ubqln水平的升高是否对小鼠脑缺血后的神经保护作用，(2)寻找能够上调Ublqn蛋白表达的化合物并验证其在中风小鼠中的治疗效果，(3)确定Ubqln在缺血性中风中诱导神经保护的机制。

 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 reactive oxygen and nitrogen species, which cause protein misfolding and aggregation. However, the role of aberrant protein clearance on the outcome of ischemic stroke remains far from being understood. Ubiquilin (Ubqln) is a ubiquitin-like protein that inhibits hypoxia-, nutrient starvatin- and protein misfolding-induced cell death. To understand the role of Ubqln in neuronal repair following ischemic stroke, we recently generated Ubqln transgenic and conditional knock-out mouse models and with the animals, we have found that overexpression of Ubqln protects neurons against oxidative stress and ischemia-caused brain injury while knockout of the gene exacerbates cerebral ischemia-caused neuronal damage and delays functional recovery. Although these observations confirm that Ubqln is a therapeutic target, transgenic manipulation-caused overexpression of Ubqln occurs prior to the event of ischemic stroke and it remains unknown whether delayed Ubqln overexpression in post-ischemic brains is still beneficial. In this revised proposal, we hypothesize that delayed elevation of Ubqln, within a clinically relevant time window following ischemic strok, reduces neuronal injury and enhances animal functional recovery. To test this hypothesis, the following specific aims will be pursued: (1) To determine whether elevation of Ubqln level in post-ischemic brains is neuroprotective in mice, (2) To identify the compounds that can upregulate Ublqn protein expression and validate their therapeutic effect in stroke mice, and (3) To identify the mechanisms underlying Ubqln-induced neuroprotection in ischemic stroke.