Constructing a Conditional Slc7a11 (xCT) Null Mouse

描述(申请人提供)：脑缺血对大脑造成的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过度刺激、氧化应激以及炎症因子介导的。我们的实验室使用体外缺血半暗带模型证明，星形胶质细胞介导的XC系统(胱氨酸/谷氨酸逆向转运体)的变化有助于炎症性(IL-12介导的)缺氧性神经元损伤的发生和发展。因此，我们相信系统XC-有可能成为治疗中风的新靶点。然而，为了验证这一假设，我们的结果必须在体内得到证实。文献中描述了SLC7a11(SUT)基因(编码XCT的轻链，决定XC系统底物特异性的轻链)自然功能突变的小鼠和XCT缺失突变小鼠。然而，这些都是全球淘汰赛。到目前为止，还不存在该等位基因的组织特异性敲除。因此，该项目的总体目标是开发(目标1)和鉴定(目标2)星形胶质细胞特异性的SLC7a11基因条件性敲除小鼠，以供在体内最终使用。

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.