Role of ubiquilin in ischemic stroke

 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。中风与活性氧和氮的过度产生有关，这导致蛋白质错误折叠和聚集。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（Ubiquilin，Ubqln）是一种泛素样蛋白，能抑制缺氧、营养饥饿和蛋白质错误折叠诱导的细胞死亡。为了了解Ubqln在缺血性中风后神经元修复中的作用，我们最近产生了Ubqln转基因和条件性敲除小鼠模型，并且使用动物，我们发现Ubqln的过表达保护神经元免受氧化应激和缺血引起的脑损伤，而基因敲除加剧脑缺血引起的神经元损伤并延迟功能恢复。尽管这些观察结果证实Ubqln是治疗靶点，但转基因操作引起的Ubqln过表达发生在缺血性中风事件之前，并且仍然不清楚缺血后脑中延迟的Ubqln过表达是否仍然有益。在这个修订后的提案中，我们假设缺血性中风后临床相关时间窗内Ubqln的延迟升高可以减少神经元损伤并增强动物功能恢复。为了检验这一假设，将追求以下具体目标：（1）确定缺血后脑中Ubqln水平的升高是否在小鼠中具有神经保护作用，（2）鉴定可以上调Ublqn蛋白表达的化合物并验证其在中风小鼠中的治疗效果，以及（3）鉴定缺血性中风中Ubqln诱导的神经保护作用的潜在机制。

 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.