THE ROLE OF BHLH GENES IN GLIOGENESIS AND GLIOMA BIOLOGY

本提案概述了一系列旨在探索正常和转化胶质细胞中基本螺旋-环-螺旋（bHLH）转录因子表达和功能之间关系的实验。由bHLH基因转录的蛋白质调节许多细胞类型的发育程序，如神经元和肌肉，并在相应谱系的肿瘤中表达。它们在肿瘤中的表达已被证明对诊断和预后以及理解细胞周期控制缺陷的机制具有重要意义。神经胶质肿瘤在很大程度上是无法治愈的，因为它们的细胞能够在大脑中不受控制地增殖和迁移。神经胶质祖细胞在大脑中分化、增殖和迁移，但以一种受控制的方式。目前尚不清楚这些正常的控制机制是如何在神经胶质肿瘤细胞中被解除调控的。由于缺乏对控制胶质细胞发育、增殖和迁移的特定基因的理解，胶质祖细胞生物学及其向胶质瘤细胞生物学转化的研究受到了阻碍。与其他细胞类型不同，bHLHs基因在胶质细胞中的表达，胶质细胞特异性基因尚未报道。该提案将i)表征已知bHLH基因在胶质细胞和胶质瘤中的表达模式，li)鉴定和克隆胶质特异性bHLH基因，iii)进行功能分析，以确定bHLH基因表达对胶质祖细胞和肿瘤细胞分化、迁移和增殖的影响。该建议的中心假设是bHLH功能的失调通过促进或未能控制肿瘤细胞的迁移、分化和增殖来促进神经胶质肿瘤表型。预计这些研究将为神经胶质和胶质瘤生物学的持续研究提供有力的工具，并通过提供更好的诊断和预后标记以及新疗法的潜在靶点，转化为改善胶质瘤患者的临床管理。

This proposal outlines a set of experiments designed to explore the relationship between the expression and function of basic helix-loop-helix (bHLH) transcription factors in normal and transformed glial cells. The proteins transcribed by bHLH genes regulate developmental programs in many cell types, such as neurons and muscle, and are expressed in tumors of the corresponding lineages. Their expression in tumors has been shown to be of significance for diagnosis-and prognosis and understanding mechanisms of defective cell-cycle control. Glial tumors are largely incurable because their cells are capable of unregulated proliferation and migration in the brain. Glial progenitor cells differentiate, proliferate and migrate in the brain, but in a controlled fashion. It is not known how these normal control mechanisms are deregulated in glial tumor cells. The study of glial progenitor cell biology, and its translation to glioma cell biology, is hampered by a lack of understanding of specific genes that control glial cell development, proliferation and migration. Unlike other cell types, the expression of bHLHs genes in glia, glial specific genes have not been reported. This proposal will i) characterize the expression patterns of known bHLH genes in glia and gliomas, li) identify and clone glial specific bHLH genes, and iii) perform functional assays to determine the effects of bHLH gene expression on glial progenitor and tumor cell differentiation, migration and proliferation. The central hypothesis of this proposal is that deregulated bHLH function contributes to glial tumor phenotype by promoting, or failing to control, tumor cell migration, differentiation, and proliferation. It is expected that these studies will offer powerful tools for the continued study of glial and glioma biology, and translate into improved clinical management of glioma patients by providing better diagnostic and prognostic markers and potential targets for novel therapies.