Regulation of Basic Fibroblast Growth Factor Gene Expressionin Reactive and Neoplastic Astrocytes

构成神经系统的两种主要细胞类型是神经元和神经胶质细胞。神经胶质细胞和神经细胞的发生、分化和成熟被认为是由个体发育阶段表达的蛋白质(生长因子)控制的。生长因子的受控表达也可能是成人神经系统在学习或再生神经组织(细胞刺激)期间发生可塑性的基础。生长因子的异常表达与正常胶质细胞向成瘤胶质瘤细胞的转化有关。因此，为了了解神经组织的发育、成体可塑性和致瘤转化，阐明编码生长因子蛋白的基因表达的机制是必不可少的。其中一种蛋白质是碱性成纤维细胞生长因子(BFGF)。阐明编码碱性成纤维细胞生长因子蛋白的基因表达的控制机制是当务之急。对这种蛋白质的调控知之甚少，这种蛋白质对神经和神经胶质的发育和可塑性至关重要。PI表明，在静止(未分裂)的胶质细胞到活跃(活跃分裂)的胶质细胞的可逆转变过程中，bFGF基因的表达一过性增加。胶质细胞的这种可逆激活被认为在神经发育和支持成年神经可塑性方面发挥了作用。PI还表明，在不可逆转化的致瘤性胶质瘤细胞中，bFGF基因的表达永久增加。在这两种情况下，碱性成纤维细胞生长因子基因表达的增加导致了神经胶质细胞生物学上的改变(短暂和永久的细胞增殖诱导)。本项目的总体目标是确定上述碱性成纤维细胞生长因子基因表达变化的分子机制。对碱性成纤维细胞生长因子基因的分析表明，与其他基因相比，该基因的调控机制有根本的不同，新的调控机制参与了对碱性成纤维细胞生长因子基因的调控。对这些机制的识别将有助于更好地理解控制发育中和成人神经系统中神经胶质细胞生物学的分子事件。

The two major cell types that form the nervous system are neurons and glial cells. Genesis of glial and neuronal cells, their differentiation and maturation in developing nervous system are thought to be controlled by proteins (growth factors) expressed at individual developmental stages. Controlled expression of growth factors may also underlie the plasticity that occurs in the adult nervous system during learning or regeneration of nervous tissue (stimulation of cells). Aberrant expression of growth factors has been implicated in the transformation of normal glial cells to tumorigenic glioma cells. Hence, to understand development, adult plasticity of the nervous tissue, and tumorigenic transformation it is essential to elucidate mechanisms that control expression of genes encoding growth factor proteins. One such protein is basic fibroblast growth factor (bFGF). Elucidation of the mechanisms controlling expression of the gene that encodes the bFGF protein is of the highest priority. Very little is known about regulation of this protein which is critical for neural and glial development and plasticity. The PI's have revealed that expression of the BFGF gene is transiently increased during reversible transition of quiescent (nondividing) glial cells to reactive (actively dividing) glia. Such reversible activation of glia is thought to play a role in neural development and in the support of adult neural plasticity. The PI has also shown that expression of the bFGF gene is permanently increased in irreversibly transformed tumorigenic glioma cells. In both cases increased expression of bFGF gene was responsible for the changes in the biology of glia (transient and permanent induction of cell proliferation). The overall aim of this project is to determine the molecular mechanisms underlying the above-mentioned changes in bFGF gene expression. The analysis of the bFGF gene has indicated that there are fundamental differences in the mechanisms by which t his gene is regulated as compared to other genes, and that novel mechanisms are involved in the regulation of bFGF gene. Identification of those mechanisms will lead to a better understanding of the molecular events controlling the biology of glial cells in the developing and adult nervous system.