ETIOLOGY AND PATHOBIOLOGY OF MENINGIOMAS

脑膜瘤，来源于覆盖大脑和脊髓的薄膜 是中枢神经系统最常见的肿瘤之一。 目前，负责启动和病理学的机制 脑膜瘤在很大程度上未知。 我们在这里提出一个战略， 不仅旨在阐明这种疾病的潜在基础， 还允许鉴定基因表达的下游变化， 可能会增加脑膜瘤的侵袭性和复发机会。 我们 这个建议的工作假设是脑膜瘤是由丢失引起的， 位于22号染色体上的“肿瘤抑制”基因的功能。 我们称 这是脑膜瘤易感位点（MSL）。 广泛、长期 拟议研究的目标是确定和充分界定 该候选肿瘤抑制基因的功能，并确定其在 负调节细胞增殖。 为了实现这一目标，我们建议 分离和表征代表msl基因的cDNA克隆，以及 作为其他功能重要的基因，其表达缺失/改变 相对于它们的正常前体，软脑膜细胞， 为此，我们构建了“消减”cDNA文库， 通过使用以下培养物富集msl基因的候选序列： 本实验室建立的原代软脑膜细胞， 两个脑膜瘤细胞系。 用以下筛选这些消减文库： 减影，软脑膜富集探针已经确定，并将 继续为MSL基因和其他感兴趣的基因提供候选物。 这些cDNA克隆的特征如下： 和表达的组织特异性分析;（B）寻找缺失 或脑膜瘤的基因组DNA中这些序列的重排;（c） 一组其他脑肿瘤的RNA分析，特别是那些 与NF 2疾病相关，以解决这些大脑 肿瘤可以共享共同的转化途径;（d）DNA转染 研究这些基因在抑制 细胞生长或诱导分化。最终目标是 使用柔脑膜细胞产生机制的信息 肿瘤发生的有效诊断，筛查和治疗 脑膜瘤

Meningiomas, derived from the thin membrane covering the brain and spinal cord, are one of the most common tumors of the central nervous system. Currently, the mechanisms responsible for the initiation and pathology of meningiomas are largely unknown. We propose here a strategy that is designed to not only elucidate the underlying basis for this disease, but also allow the identification of downstream changes in gene expression that could contribute to meningioma aggressivity and chance for recurrence. Our working hypothesis for this proposal is that meningiomas result from loss of function of a "tumor suppressor" gene located on chromosome 22. We call this the meningioma susceptibility locus (msl). The broad, long-term objective of the proposed research is to identify and fully define the function of this candidate tumor suppressor gene, and determine its role in negatively regulating cellular proliferation. Toward that goal we propose to isolate and characterize cDNA clones representing the msl gene, as well as other functionally important genes whose expression is missing/altered in meningiomas relative to their normal precursor, leptomeningeal cells. To do this we have constructed "subtraction" cDNA libraries that are enriched for candidate sequences for the msl gene, by using cultures of primary leptomeningeal cells established in this laboratory together with two meningioma cell lines. Screening of these subtraction libraries with subtracted, leptomeningeal-enriched probes have identified and will continue to provide candidates for the msl gene and others of interest. These cDNA clones will be characterized as follows: (a) chromosomal mapping and analysis of tissue specificity of expression; (b) search for deletions or rearrangements of these sequences in genomic DNA of meningiomas; (c) analysis of RNA from a panel of other brain tumors, particularly those associated with the disorder NF2, to address the proposal that these brain tumors may share a common pathway of transformation; (d) DNA transfection protocols to examine the possible role of these genes in the suppression of cell growth or the induction of differentiation. The ultimate goal is to use information generated on the mechanism of leptomeningeal cell tumorigenesis towards the effective diagnosis, screening and therapy of meningiomas.