Novel Nuclear Signaling Mechanisms in Control of FGF-2 Expression in 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。神经系统中胶质细胞和神经元细胞的发生、分化和成熟被认为是由特定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（刺激细胞分裂、改变细胞形状和细胞间接触）过程中发生的可塑性的基础。生长因子的异常表达与正常胶质细胞向致瘤性胶质瘤细胞的转化有关。因此，为了了解神经系统组织的发育、成体可塑性和致瘤性转化，阐明生长因子蛋白表达和功能的控制机制是必要的。碱性成纤维细胞生长因子（bFGF或FGF-2）就是这样一种蛋白质，对神经元和胶质细胞的发育、可塑性和致瘤性转化至关重要。调控bFGF表达和功能的机制的阐明是当务之急。Stachowiak博士实验室的研究表明，在静止（非分裂）胶质细胞向反应（积极分裂）胶质细胞转变的过程中，bFGF的表达会短暂增加。这种胶质细胞的可逆激活在神经发育和支持成体神经可塑性方面起着重要作用。Stachowiak博士的实验室也表明，bFGF基因的表达在不可逆激活的致瘤性胶质细胞（胶质瘤肿瘤）中永久增加。该项目的总体目标是确定上述bFGF基因表达变化的分子机制。研究表明，与其他基因相比，bFGF基因的调节机制存在根本差异。这些机制的识别将有助于更好地理解神经系统发育和可塑性的分子遗传控制。

9728923 STACHOWIAK The two major cell types that form the nervous system are neurons and glia. Genesis of glial and neuronal cells, and their differentiation and maturation in the developing nervous system are thought to be controlled by proteins (growth factors) expressed at specific developmental stages. Controlled expression of growth factors may also underlie plasticity that occurs in the adult nervous system during learning or regeneration of nervous tissue (stimulation of cell division, changes in cell shape and in contacts between 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 nervous system tissue, and tumorigenic transformation it is essential to elucidate mechanisms that control expression and function of growth factor proteins. Basic fibroblast growth factor (bFGF or FGF-2) is one such protein that is critical for neuronal and glial development, plasticity, and tumorigenic transformation. Elucidation of the mechanism controlling bFGF expression and function is of the highest priority. Studies in Dr. Stachowiak's laboratory have revealed that expression of bFGF is transiently increased during the shift of quiescent (non-dividing) glial cells to reactive (actively dividing) glia. Such reversible activation of glia plays an important role in neural development and in the support of adult neural plasticity. Dr. Stachowiak's laboratory has also shown that the expression of the bFGF gene is permanently increased in irreversibly activated tumorigenic glia (glioma tumors). The overall aim of this project is to determine the molecular mechanisms underlying the above-mentioned changes in bFGF gene expression. The investigation has indicated that there are fundamental differences in the mechanisms by which the bFGF gene is regulated as compared to other genes. Identification of those mechanism will lead to a better understanding of the molecular-genetic control of the development and plasticity of the nervous system.