APOLIPOPROTEIN E AND THE ISCHEMIC BRAIN

描述（改编自申请人的摘要）：中风仍然是一个主要的 这是美国公共卫生的一个问题。 至少有三 载脂蛋白E的人类等位基因（2、3或4）。 最近的证据表明 患者的载脂蛋白E（Apo E）基因型是一个风险因素， 治疗中枢神经系统损伤的不良后果 患者 心肺旁路手术，以及那些从 颅内出血性中风或头部外伤， 如果他们携带载脂蛋白E4等位基因。 很少有人知道关于 载脂蛋白E与脑缺血机制的相互作用 损害 使用暂时性大脑中动脉恢复模型 闭塞，这项研究将检查载脂蛋白E缺乏的小鼠， 携带不同人类载脂蛋白E等位基因的基因工程小鼠。两 已经产生了表达人载脂蛋白E 同种型。 两者都携带编码载脂蛋白E蛋白的人DNA序列。 一种菌株利用人转基因载脂蛋白E启动子，而另一种菌株利用人转基因载脂蛋白E启动子。 利用天然鼠启动子。 携带人类启动子的小鼠 证明神经元和神经胶质细胞中存在载脂蛋白E免疫反应性（类似于 在人类中观察到的模式）。 携带鼠启动子染色的小鼠 ApoE仅在神经胶质细胞中呈阳性（与野生型中观察到的模式相似）。 型啮齿动物）。 我们建议定义：1）如果这些突变小鼠表现出 脑血管系统中肉眼异常的频率差异; 2）如果 人载脂蛋白E4对小鼠局灶性缺血的剂量依赖性作用 结果; 3）如果脑梗死面积的差异归因于 载脂蛋白E基因型; 4）如果缺血性结局中等位基因特异性差异 归因于梗死风险组织体积的差异 5）如果ApoE对中风的作用是介导的， 通过中枢神经系统表达或从外周; 6）如果 缺血前ApoE的神经元内表达是分化 Apo等位基因对缺血性结局的影响; 8）如果Apo E免疫反应性 在局灶性缺血性病变的半影区的神经元和神经胶质细胞中， 9）如果人的Apo E等位基因改变了人的Apo E基因， 对短暂局灶性缺血损伤的凋亡反应。 我们认为这 信息将具有实质性价值， 载脂蛋白E对缺血性结局的作用机制及治疗提供依据 中风的治疗方法

DESCRIPTION (Adapted from Applicant's Abstract): Stroke remains a major problem for public health in the United States. There are at least three human alleles for apolipoprotein E (2, 3, or 4). Recent evidence indicates that the patient's genotype for apolipoprotein E (Apo E) is a risk factor for poor outcome from central nervous system injury. Patients undergoing cardiopulmonary bypass surgical procedures, and those recovering form intracranial hemorrhagic stroke or head trauma have poorer neurologic outcomes if they carry the apo E4 allele. Little is known regarding potential interactions between Apo E and mechanisms of ischemic brain damage. Using a recovery model of temporary middle cerebral artery occlusion, this research will examine mice deficient for Apo E and genetically engineered mice carrying different alleles of human Apo E. Two distinctly different strains have been created which express the human Apo E isoforms. both carry the human DNA sequence coding for the Apo E protein. One strain utilizes the human transgenic Apo E promoter while the other utilizes the native murine promoter. Mice carrying the human promoter demonstrate Apo E immunoreactivity in both neurons and glial (similar to the pattern observed in humans). Mice carrying the murine promoter stain positive for Apo E only in glia (similar to the pattern observed in wild type rodents). We propose to define: 1) If these mutant mice exhibit a differential frequency of gross anomalies in the cerebral vasculature; 2) If human Apo E4 causes a dose dependent effect on murine focal ischemic outcome; 3)If there is a difference in cerebral infarct size attributable to the Apo E genotype; 4) If allele specific differences in ischemic outcome ar attributable to differences in volume of tissue at risk for infarction during the ischemic insult; 5) If the effect of ApoE on stroke is mediated via central nervous system expression or from the periphery; 6) If pre-ischemic intraneuronal expression of Apo E is required for differential effects of the Apo alleles on ischemic outcome; 8) If Apo E immunoreactivity in neurons and glia in the penumbra of a focal ischemic lesion varies as a result of the Apo E allele; and 9) If the human Apo E allele alters the apoptotic response to brief focal ischemic insults. We believe that this information would be of substantial value in defining both the relevance of Apo E mechanisms to ischemic outcome and provide a basis for therapeutic approaches to the treatment of stroke.