MOLECULAR BIOLOGY OF CENTRAL NERVOUS SYSTEM MYELINATION

髓鞘形成是一个重要的发育过程，当改变时， 会导致严重的神经功能障碍 我们的总体目标是 研究的目的是为了更好地了解 髓鞘蛋白在中枢神经系统的髓鞘形成中起作用 （CNS）。 此外，髓磷脂蛋白质在神经元中的功能也不清楚。 少突胶质细胞，CNS的髓鞘形成细胞， 将被审查。 编码髓鞘碱性蛋白（MBP）的基因将 在髓鞘形成障碍的鼠突变髓鞘缺陷（MLD）中进行分析。 mld MBP基因与其上游的 含有3'端倒位的基因。 的DNA序列 围绕反转/复制的断点的将是 确定，以努力识别与 重组事件负责基因重排。 的mld MBP基因表达水平降低， 发展时间表将采用几种体外和体内方法， 以确定这种改变的MBP表达的基础。 的 髓鞘形成障碍鼠突变jimpy导致蛋白脂质（PLP）， DM-20蛋白缺乏、CNS髓鞘形成不足和少突胶质细胞 死亡 转基因jimpy动物将被产生，表达 只有PLP或DM-20，试图确定这些蛋白质的作用 对这些动物的髓鞘形成和少突胶质细胞存活有什么影响。 还将努力将髓磷脂蛋白基因在 转基因小鼠 将产生的动物包含一个巨大的臼齿 参与调节髓鞘蛋白基因的顺式区过量 表情 通过功能性地消耗髓鞘中的少突胶质细胞 蛋白质基因反式激活蛋白，抑制 这些基因的转录活性应该发生。

Myelination is a critical developmental process that, when altered, results in severe neurological dysfunction. The overall goal of our research is directed toward obtaining a better understanding of the role myelin proteins play in the myelination of the central nervous system (CNS). Additionally, the function of myelin proteins in the differentiation of oligodendrocytes, the myelinating cell of the CNS, will be examined. The gene encoding the myelin basic protein (MBP) will be analyzed in the dysmyelinating murine mutant myelin deficient (mld). The mld MBP gene is organized as a tandem duplication with the upstream gene containing an inversion of its 3' region. The DNA sequence surrounding the breakpoints of the inversion/duplication will be determined in an effort to identify regions associated with the recombinational events responsible for the gene rearrangement. The mld MBP gene is expressed at decreased levels and on an abnormal developmental schedule. Several in vitro and in vivo approaches will be taken to determine the basis of this altered MBP expression. The dysmyelinating murine mutation jimpy results in proteolipid (PLP) and DM-20 protein deficiencies, CNS hypomyelination, and oligodendrocyte death. Transgenic jimpy animals will be generated that express either only PLP or DM-20 in an attempt to determine the effect these proteins have on myelination and oligodendrocyte survival in these animals. Efforts will also be made to inactivate the myelin protein genes in transgenic mice. Animals will be generated that contain a vast molar excess of the cis regions involved in regulating myelin protein gene expression. By functionally depleting oligodendrocytes of the myelin protein genes trans-activator proteins, inhibition of the transcriptional activity of these genes should occur.