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

形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元细胞的发生、它们在发育神经系统中的分化和成熟被认为是由在各个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神经组织再生（细胞刺激）期间发生的可塑性的基础。 生长因子的异常表达与正常神经胶质细胞向致瘤性神经胶质瘤细胞的转化有关。 因此，要了解发育，成人可塑性的神经组织，和致瘤性转化，它是必不可少的阐明机制，控制基因编码的生长因子蛋白的表达。 一种这样的蛋白质是碱性成纤维细胞生长因子（bFGF）。 阐明控制编码bFGF蛋白的基因表达的机制是最优先的。 关于这种蛋白的调节知之甚少，这种蛋白对神经和神经胶质的发育和可塑性至关重要。 PI已经揭示，在静止（非分裂）神经胶质细胞向反应性（活跃分裂）神经胶质细胞的可逆转变期间，BFGF基因的表达瞬时增加。 神经胶质细胞的这种可逆激活被认为在神经发育和支持成人神经可塑性中起作用。PI还显示，bFGF基因的表达在不可逆转化的致瘤性神经胶质瘤细胞中永久性增加。 在这两种情况下，bFGF基因的表达增加是负责神经胶质细胞的生物学变化（细胞增殖的瞬时和永久诱导）。 本项目的总体目标是确定上述bFGF基因表达变化的分子机制。 对bFGF基因的分析表明，与其他基因相比，该基因的调节机制存在根本性差异，并且新的机制参与bFGF基因的调节。 这些机制的识别将导致更好地了解控制发育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.