Constructing a Conditional Slc7a11 (xCT) Null Mouse

描述（由申请人提供）：脑缺血引起的脑损伤是一个主要的公共卫生问题。研究已经确定与脑缺血相关的脑损伤是由兴奋性氨基酸受体的过度刺激、氧化应激以及炎症因子介导的。我们的实验室证明-使用缺血半暗带的体外模型-星形胶质细胞介导的系统xc-（胱氨酸/谷氨酸反向转运蛋白）的改变有助于炎症（IL-12介导的）缺氧神经元损伤的发展和进展。因此，我们相信系统xc-有可能成为一个新的治疗中风的目标。然而，为了验证这一假设，我们的结果必须在体内得到证实。在文献中描述了在Slc 7a 11（sut）基因中携带自然功能缺失突变的小鼠-其编码xCT，在系统xc中指示底物特异性的轻链-和xCT无效突变小鼠。然而，这些都是全球淘汰赛。到目前为止，还不存在针对该等位基因的组织特异性敲除。因此，本项目的总体目标是开发（目标1）和表征（目标2）星形胶质细胞特异性条件性敲除小鼠的Slc 7a 11基因的最终体内使用。 公共卫生相关性：与脑缺血（中风）相关的发病率仍然是一个巨大的情感和经济负担，这在很大程度上是由于治疗选择的空白，以防止继发性损伤。我们的论点是，成功完成这项申请[即，Sca 711（xCT）条件性敲除动物的成功产生]将允许我们评估我们的假设的可行性，即星形胶质细胞系统xc-（胱氨酸/谷氨酸转运蛋白）是中风中的新治疗靶点。

DESCRIPTION (provided by applicant): Injury to the brain caused by cerebral ischemia is a major public health concern. Studies have determined that the brain damage associated with cerebral ischemia is mediated by over-stimulation of excitatory amino acid receptors, oxidative stress, as well as inflammatory factors. Our laboratory demonstrated - using an in vitro model of the ischemic penumbra - that astrocyte-mediated alterations in system xc- (cystine/glutamate antiporter) contribute to the development and progression of inflammatory (IL-12-mediated) hypoxic neuronal injury. Thus, we believe that system xc- has the potential to be a novel therapeutic target for stroke. However, to validate this hypothesis, our results must be confirmed in vivo. Mice harboring a natural loss of function mutation in the Slc7a11 (sut) gene - which encodes for xCT, the light chain dictating substrate specificity in system xc- - and xCT null mutant mice have been described in the literature. However, these are global knockouts. To date no tissue-specific knockout for this allele exists. Hence, the overall goal of this project is to develop (Aim 1) and characterize (Aim 2) an astrocyte-specific conditional knockout mouse of the Slc7a11 gene for the ultimate use in in vivo. PUBLIC HEALTH RELEVANCE: Morbidity associated with cerebral ischemia (stroke) remains a huge emotional and economic burden due in large part to a void in treatment options to protect against secondary injury. It is our contention that successful completion of this application [i.e., the successful generation of a Scla711 (xCT) conditional knockout animal] will allow us to assess the viability of our hypothesis that astrocyte system xc- (cystine/glutamate transporter) is a novel therapeutic target in stroke.