HYPOMYELINATION IN TRANSGENICS--MODEL FOR PML

JC病毒是一种广泛存在于人类中的人乳头状病毒 人口。感染通常发生在儿童时期，通常 是亚临床的。然而，在少数患者中，其 免疫力受到疾病、遗传性疾病或 治疗，JC被认为是致命的 脱髓鞘病进行性多灶性白质脑病 (PML)。虽然PML很少见，但发病率有所上升 最近，由于大量免疫受损的艾滋病病毒 病人。JC病毒颗粒可以从脑部病变中分离出来 少突胶质细胞异常的PML患者 和星形胶质细胞。脱髓鞘的原因是 少突胶质细胞，中央的髓鞘产生细胞 神经系统。含有早期区域的转基因小鼠 已经产生了JC病毒，有两个品系的小鼠有一个 中枢神经系统的髓鞘障碍。这些老鼠 因此为人类脱髓鞘提供了一个动物模型 疾病。预计对转基因小鼠的分析将 深入了解PML所涉及的生化过程。 对这些小鼠的初步分析显示，它们在 少突胶质细胞。更多藏匿自然发生的小鼠 将产生JC变种，并将对老鼠进行分析 确定组织和发育的特定模式 JCV早期区域的表达。髓磷脂的分析 特殊蛋白髓鞘碱性蛋白(MBP)、蛋白-脂蛋白 (PLP)和髓鞘相关糖蛋白(MAG) 已执行。对于MBP和PLP，将在 在RNA和蛋白质水平上的几个发育阶段。 对于没有核酸探针的MAG，表达 将仅限于蛋白质水平。我们将尝试 鉴定和分离结合并调节的蛋白质因子 JC早期区域的表达。预计其中一些 这些相同的因素也将调节髓鞘的表达- 特定的蛋白质。

JC virus (JCV) is human papovavirus that is widespread in human populations. Infections usually occur in childhood and normally are subclinical. However, in a small number of patients whose immunity has been compromised by disease, genetic disorders, or therapy, JC has been implicated as a causative agent in the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). Although PML is rare, the incidence has risen somewhat recently because of the large pool of immuno-compromised AIDS patients. JC viral particles can be isolated from brain lesions of patients with PML, in which there are abnormal oligodendrocytes and astrocytes. Demyelination is caused by destruction of oligodendrocytes, the myelin-producing cells of the central nervous system. Transgenic mice containing the early region of JC virus have been generated, and two lines of mice have a dysmyelination in the central nervous system. These mice therefore provide an animal model for this human demyelinating disease. It is anticipated that analyses of the transgenic mice will lead to insight into the biochemical processes involved in PML. Initial analyses of these mice demonstrated expression in oligodendrocytes. Additional mice harboring naturally occurring JC variants will be generated and mice will be analyzed to determine the tissue- and development-specific patterns of expression of the JCV early regions. Analyses of the myelin specific proteins myelin basic protein (MBP), proteo-lipid protein (PLP), and myelin-associated glycoprotein (MAG) will be performed. For MBP and PLP, expression will be determined at several stages of development at both the RNA and protein levels. For MAG, where a nucleic acid probe is not available, expression will be limited to the protein level. Attempts will be made to identify and isolate protein factors that bind to, and regulate expression of, the JC early region. It is anticipated that some of these same factors also will regulate expression of the myelin- specific proteins.