APOLIPOPROTEIN E AND THE ISCHEMIC BRAIN

描述(改编自申请者摘要)：中风仍然是一个主要问题 美国的公共卫生问题。至少有三个 人类载脂蛋白E的等位基因(2、3或4)。最近的证据表明 患者的载脂蛋白E(Apo E)基因是一个危险因素 对于中枢神经系统损伤的不良结局。接受治疗的患者 体外循环手术程序，以及正在康复的程序 颅内出血性中风或头部创伤的神经学状况较差 如果他们携带载脂蛋白E4等位基因，结果。我们对此知之甚少 载脂蛋白E与脑缺血机制的潜在相互作用 损坏。暂时性大脑中动脉恢复模型的建立 这项研究将检查载脂蛋白E和载脂蛋白E缺乏的小鼠 携带人类载脂蛋白E-2不同等位基因的转基因小鼠 已经创造了表达人类载脂蛋白E的明显不同的菌株 异构体。两者都携带编码载脂蛋白E的人类DNA序列。 一株利用人转基因载脂蛋白E启动子，而另一株利用人转基因载脂蛋白E启动子 利用天然的小鼠启动子。携带人类启动子的小鼠 在神经元和神经胶质细胞中均显示载脂蛋白E免疫反应(类似于 在人类身上观察到的模式)。携带小鼠启动子染色的小鼠 载脂蛋白E仅在神经胶质细胞中呈阳性(类似于在野外观察到的模式 啮齿类动物)。我们建议定义：1)如果这些突变小鼠表现出 脑血管系统大体异常的不同频率；2)如果 人载脂蛋白E4对小鼠局灶性脑缺血的剂量依赖效应 结果；3)如果在脑梗塞面积上有差异可归因于 载脂蛋白E基因型；4)如果等位基因特异性差异在缺血预后中 可归因于有梗死危险的组织体积的差异 5)载脂蛋白E在卒中中的作用 通过中枢神经系统表达或来自外周；6)如果 缺血前载脂蛋白E在神经元内的表达是分化所必需的 载脂蛋白E等位基因对缺血预后的影响8)载脂蛋白E免疫反应 局灶性脑缺血损伤半影区的神经元和神经胶质细胞的变化 9)如果人类的载脂蛋白E等位基因改变了 对短暂性局灶性脑缺血损伤的细胞凋亡反应。我们相信这一点 信息将在界定以下两个方面的相关性方面具有实质性价值 载脂蛋白E机制对脑缺血转归的影响及治疗依据 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.