Activation of Plp gene expression in oligodendrocytes

描述（由申请方提供）：髓鞘由CNS中的少突胶质细胞产生，其在动作电位沿着轴突传播中的作用已得到充分研究。髓磷脂是神经胶质细胞质膜的延伸，但它在生物化学上非常不同。这种差异的一部分可以归因于特异性靶向髓鞘膜的蛋白质的组成。这些蛋白质之一，髓鞘蛋白脂质蛋白（PLP）占成人CNS髓鞘中发现的总蛋白质的近50%。基因的表达受到严格的调控。在人类中，P/p基因（位于X染色体上）的突变已被证明与X连锁髓鞘形成障碍（PMD）和某些类型的痉挛性截瘫（SPG-2）有关。髓鞘形成障碍可由P/p基因表达水平升高或缺乏表达引起。因此，P/p的准确表达是至关重要的，阐明其调控将有助于破译可能在某些PMD/SPG-2患者中发生突变的重要转录调控元件。另一方面，阐明基因调控的机制可以提供对PMD/SPG-2的替代原因的洞察，这不是由P/p基因突变引起的。 此外，重要的是要了解gone是如何调节的，以帮助促进脱髓鞘疾病患者的髓鞘再生过程。多发性硬化症是最常见的脱髓鞘疾病，通常发生在成年人中，基本上在CNS发育中的活跃髓鞘形成期已经结束之后。缺失-转染分析已经证实了位于第一内含子内的调节序列的重要性，所述调节序列对于调节P/p gone表达是必需的。这些元素之一，所谓的ASE，抗沉默剂/增强剂，似乎导致P/p基因表达的显着增加期间（和之后）的髓鞘形成期的中枢神经系统的发展。我们相信多种因子在ASE上组装形成一种立体特异性的核蛋白结构，称为“增强体”。为了了解ASE是如何介导P/p gone的激活的，已经提出了以下具体目标：1）进一步表征ASE，一个位于内含子1 DNA中的正顺式作用调节元件，它促进少突胶质细胞中P/p基因的高水平表达; 2）鉴定在ASE上形成转录调节复合物的核因子; 3）阐明ASE核蛋白复合物激活少突胶质细胞P/pgone表达的机制。

DESCRIPTION (provided by applicant): Myelin is produced by oligodendrocytes in the CNS, and its role in propagation of the action potential along the axon has been well studied. Myelin is an extension of the glial cell's plasma membrane, however it is biochemically very different. Part of this difference can be attributed to the composition of the proteins specifically targeted to the myelin membrane. One of these proteins, the myelin proteolipid protein (PLP) accounts for almost 50% of the total protein found in adult CNS myelin. Expression of the gene is tightly regulated. In humans, mutations in the P/p gene (which resides on the X chromosome) have been shown to be associated the X-linked dysmyelinating disorder Pelizaeus-Merzbacher disease (PMD), and some types of spastic paraplegia (SPG-2). Dysmyelination can arise from either elevated levels of P/p gene expression or lack of expression. Thus accurate expression of the P/p is critical, and elucidation of its regulation will be helpful in deciphering essential transcription regulatory elements that may be mutated in some people with PMD/SPG-2. On the other hand, elucidation of the mechanisms whereby the gene is regulated could provide insight into alternative causes of PMD/SPG-2, which do not arise from P/p gene mutations. Furthermore, it is important to understand how the gone is regulated, in order to help promote the remyelination process in people with demyelinating diseases. Multiple sclerosis, the most common demyelinating disease, generally occurs in adults substantially after the active myelination period in CNS development has ended. A deletion-transfection analysis has confirmed the importance of regulatory sequences located within the first intron that are essential for regulating P/p gone expression. One of these elements, the so-called ASE, for antisilencer/enhancer, appears to cause a dramatic increase in P/p gene expression during (and after) the myelination period of CNS development. We believe that multiple factors assemble on the ASE to form a stereospecific nucleoprotein structure termed an "enhanceosome." To understand how the ASE mediates P/p gone activation, the following specific aims have been proposed: 1) Characterize further the ASE, a positive cis-acting regulatory element located in intron 1 DNA, which promotes high levels of P/p gene expression in oligodendrocytes; 2) Identify the nuclear factors, which form a transcriptional regulatory complex on the ASE; 3) Elucidate the mechanism whereby the ASE nucleoprotein complex activates P/p gone expression in oligodendrocytes.