MOLECULAR BIOLOGY OF CENTRAL NERVOUS SYSTEM MYELINATION

髓鞘形成是一个关键的发育过程，当改变时， 导致严重的神经功能障碍。我们的总体目标是 研究的目的是更好地了解这一角色 髓鞘蛋白在中枢神经系统的髓鞘形成过程中发挥作用 (CNS)。此外，髓鞘蛋白在脑脊液中的作用 少突胶质细胞的分化，中枢神经系统的髓鞘细胞， 将会被检查。编码髓鞘碱性蛋白(MBP)的基因将 在髓鞘缺陷小鼠突变株(MLD)中进行分析。 MLD MBP基因被组织为与上游的串联复制 含有3‘区倒位的基因。DNA序列 围绕反转/复制的断点将是 确定的目的是为了确定与 负责基因重排的重组事件。MLD MBP基因表达水平降低，并在异常的 发育时间表。几种体外和体内的方法将是 用来确定这种改变的MBP表达的基础。这个 髓鞘障碍小鼠突变jimpy导致蛋白脂(PLP)和 DM-20蛋白缺乏、中枢神经系统髓鞘减退和少突胶质细胞 死亡。转基因的小动物将会表达其中的一个 只有PLP或DM-20试图确定这些蛋白质的影响 对这些动物的髓鞘形成和少突胶质细胞存活有影响。 还将努力使髓鞘蛋白基因失活。 转基因小鼠。将会产生含有巨大臼齿的动物 调控髓鞘蛋白基因的顺式区域过多 表情。通过功能耗尽髓鞘少突胶质细胞 蛋白基因反式激活蛋白的抑制作用 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.