TUMOR SUPPRESSION IN GLIOBLASTOMA MULTIFORME

多形性胶质母细胞瘤的肿瘤抑制

• 批准号: 2095022
• 负责人: DANIEL WEBSTER FULTS
• 金额: $ 23.59万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2095022
• 关键词: astrocytoma; chromosome deletion; chromosome translocation; genetic mapping; glioblastoma multiforme; human genetic material tag; human subject; hybrid cells; hypoxanthine phosphoribosyltransferase; loss of heterozygosity; neoplasm /cancer genetics; nucleic acid repetitive sequence; polymerase chain reaction; restriction fragment length polymorphism; sex chromosomes; southern blotting; transfection; tumor suppressor genes

Astrocytoma, the most common brain tumor in humans, typically progresses through stages of increasing malignancy to glioblastoma multiforme (GBM), an incurable, end-stage of the disease. Loss of genes that function normally to suppress cell proliferation (tumor suppressor genes) define critical steps in astrocytoma progression. The fact that deleted copies of chromosome 10 are frequently observed in GBM supports the hypothesis that one or more tumor suppressor genes located on chromosome 10 occupy crucial growth control checkpoints within the central nervous system. The long-range objective of the research program outlined here is to identify such a gene. Progress toward identifying candidate genes has been impeded by uncertainty regarding the precise chromosomal location of the suppressor locus. Deletion mapping in primary GBM tumors implicates the 10q24-10qter region as one possible site for a gene. A translocation breakpoint in a human GBM cell line, JBSA, suggests that the 10q22 region is another site. The central question now is what are the regions of 10q that contain genes capable of suppressing growth in glioblastoma cells? A functional assay is needed to test fragments of 10q for tumor cell growth suppression before molecular cloning strategies can be employed effectively to isolate candidate genes. In this research proposal, microcell fusion techniques will be used to transfer the 10q24-10qter and 10q11-10qter regions from a normal chromosome into JBSA glioblastoma cells to determine whether one or both regions suppress tumor cell growth. Tumor suppressing activity will then be tracked to a submicroscopic region of 10q using a radiation reduction strategy. In parallel with these functional assays for tumor suppression, deletion mapping in GBM patients will be continued using new chromosome 10 markers in order to define a region of chromosome 10 small enough for molecular cloning of candidate genes. Isolation of the GBM gene will advance our knowledge of cell growth control in the nervous system and may provide a target for gene therapy of astrocytomas in the future.

星形细胞瘤是人类最常见的脑肿瘤， 通过恶性程度增加到多形性胶质母细胞瘤（GBM）的阶段， 无法治愈的晚期疾病 功能基因的丧失 通常抑制细胞增殖（肿瘤抑制基因）定义为 星形细胞瘤进展的关键步骤。 删除的副本 在GBM中经常观察到10号染色体的突变支持了这一假设 位于10号染色体上的一个或多个肿瘤抑制基因 中枢神经系统内重要的生长控制检查点。 的 这里概述的研究计划的长期目标是确定 这样的基因。 鉴定候选基因的进展受到阻碍 由于不确定性的精确染色体定位的 抑制基因座 原发性胶质母细胞瘤的缺失图谱提示 10 q24 - 10 qter区域作为基因的一个可能位点。 易位 人GBM细胞系JBSA中的断裂点表明，10 q22区域 是另一个网站。 现在的核心问题是10 q的区域是什么 含有能够抑制胶质母细胞瘤细胞生长的基因 需要一种功能测定来检测肿瘤细胞10 q片段 在采用分子克隆策略之前抑制生长 有效地分离候选基因。 在这项研究计划中， 微细胞融合技术将用于转移10 q24 - 10 qter， 正常染色体10 q11 - 10 qter区域进入JBSA胶质母细胞瘤细胞 以确定是否一个或两个区域抑制肿瘤细胞生长。 然后将肿瘤抑制活性追踪到亚显微区域 10 Q的辐射减少策略。 与此同时， 用于肿瘤抑制的功能测定，GBM患者中的缺失定位 将继续使用新的染色体10标记，以确定一个 10号染色体的区域足够小，可以进行候选基因的分子克隆 基因. GBM基因的分离将促进我们对细胞增殖的认识。 神经系统中的生长控制，并可能为基因治疗提供靶点。 星形细胞瘤的治疗。