PRODUCTION OF ALTERNATIVE FGF RECEPTOR FORMS IN TUMORS

肿瘤中替代 FGF 受体形式的产生

基本信息

批准号：
7893680
负责人：
GILBERT J. COTE
金额：
$ 24.98万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-07-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7893680
关键词：
Ablation Adhesions Affect Affinity Alternative Splicing Area Astrocytes Biochemical Cell Adhesion Molecules Cell Culture Techniques Cell Line Cell physiology Cells Common Neoplasm Complex Data Development Event Exclusion Exons FGFR1 gene Fibroblast Growth Factor Fibroblast Growth Factor Receptor 1 Gene Expression Gene Targeting Genes Genetic Genomics Glioblastoma Glioma Gliomagenesis Goals Grant Growth Human Induction of Apoptosis Laboratories LacZ Genes Lead Ligands Light Link Malignant - descriptor Malignant Neoplasms Mediating Methods MicroRNAs Modeling Molecular Profiling Neuraxis Neuroglia Normal Cell Pathway interactions Play Polypyrimidine Tract-Binding Protein Process Production Property Proteins RNA RNA Processing RNA Splicing RNA-Binding Proteins Receptor Activation Receptor Signaling Research Personnel Role Signal Pathway Signal Transduction Small Interfering RNA Trans-Activators Transgenic Mice Transgenic Organisms Up-Regulation cell growth comparative extracellular genome-wide improved interest metaplastic cell transformation mouse model neoplastic cell outcome forecast overexpression programs protein expression receptor receptor expression restoration therapeutic development tool tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) are by far the most common tumor of the central nervous system and continue to be associated with a dismal prognosis. Although our understanding of genetic and biochemical changes accompanying glial cell malignancy has improved in recent years, few studies have examined the impact and mechanisms responsible for aberrant changes in RNA splicing. Because previous studies have demonstrated the aberrant RNA splicing of numerous genes associated with GBM, this is a promising new area for therapeutic development. We have focused on the fibroblast growth factor receptor 1 gene (FGFR1) because the level of a high-affinity form of FGFR1 is dramatically elevated in GBM as a result of altered expression and RNA splicing. We have linked the aberrant splicing FGFR1 RNA to a dramatic upregulation in the expression of the multifunctional RNA-binding protein, known as polypyrimidine tract binding protein (PTB). This observation led to the hypothesis that GBM-associated alterations in normal RNA splicing, including but not limited to FGFR1, act to facilitate either initiation or growth of glial tumor either initiation or growth. We propose the following Specific Aims: (1) to define the role of the FGFR1 D1-loop (included by normal splicing) in receptor signaling, (2) to confirm a functional role of aberrant FGFR1 splicing in glial cell malignancy, (3) to confirm a requirement for PTB expression in glial cell malignancy and define the specific targets of PTB action, (4) to develop a mouse model for PTB- mediated oncogenesis. Aims 1 - 3 will employ new experimental tools that allow for the specific correction of aberrant RNA splicing, the targeted ablation of gene products, and the application of genome-wide exon expression profiling. Aim 4 will employ proven transgenic approaches to establish astrocyte-specific expression of PTB. The resulting data will show whether alterations in FGFR1 RNA splicing or PTB trans-acting factor expression play a role in glial cell malignancy. A better understanding of this process may shed light on the transformation of astrocytes and provide new targets for suppressing their malignant growth.

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是迄今为止最常见的中枢神经系统肿瘤，并且仍然与不良预后相关。尽管近年来我们对胶质细胞恶性肿瘤伴随的遗传和生化变化的了解有所提高，但很少有研究探讨 RNA 剪接异常变化的影响和机制。因为之前的研究已经证明了与 GBM 相关的许多基因的异常 RNA 剪接，所以这是一个有前途的治疗开发新领域。我们重点关注成纤维细胞生长因子受体 1 基因 (FGFR1)，因为由于表达和 RNA 剪接的改变，GBM 中高亲和力形式的 FGFR1 水平显着升高。我们将异常剪接 FGFR1 RNA 与多功能 RNA 结合蛋白（称为多嘧啶束结合蛋白 (PTB)）表达的急剧上调联系起来。这一观察结果得出这样的假设：正常RNA剪接中与GBM相关的改变，包括但不限于FGFR1，起到促进神经胶质瘤的起始或生长的作用。我们提出以下具体目标：(1) 定义 FGFR1 D1 环（包括正常剪接）在受体信号转导中的作用，(2) 确认异常 FGFR1 剪接在神经胶质细胞恶性肿瘤中的功能作用，(3)确认胶质细胞恶性肿瘤中 PTB 表达的要求并确定 PTB 作用的具体靶标，(4) 开发 PTB 介导的肿瘤发生的小鼠模型。目标 1 - 3 将采用新的实验工具，对异常 RNA 剪接进行特异性校正、基因产物的靶向消融以及全基因组外显子表达谱的应用。目标 4 将采用经过验证的转基因方法来建立 PTB 星形胶质细胞特异性表达。由此产生的数据将显示 FGFR1 RNA 剪接或 PTB 反式作用因子表达的改变是否在神经胶质细胞恶性肿瘤中发挥作用。更好地理解这一过程可能有助于了解星形胶质细胞的转化，并为抑制其恶性生长提供新的靶点。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Enhancer-dependent splicing of FGFR1 alpha-exon is repressed by RNA interference-mediated down-regulation of SRp55.

FGFR1 α 外显子的增强子依赖性剪接受到 RNA 干扰介导的 SRp55 下调的抑制。

DOI：
发表时间：
2004-12-15
期刊：
影响因子：
11.2
作者：
Jin, Wei;Cote, Gilbert J
通讯作者：
Cote, Gilbert J

Mutational analysis of the GDNF/RET-GDNFR alpha signaling complex in a kindred with vesicoureteral reflux.

膀胱输尿管反流家族中 GDNF/RET-GDNFR α 信号复合物的突变分析。

DOI：
发表时间：
1998-04
期刊：
影响因子：
5.3
作者：
Shefelbine, S E;Khorana, S;Schultz, P N;Huang, E;Thobe, N;Hu, Z J;Fox, G M;Jing, S;Cote, G J;Gagel, R F
通讯作者：
Gagel, R F

Polypyrimidine tract binding protein and Notch1 are independently re-expressed in glioma.

多聚嘧啶束结合蛋白和Notch1在神经胶质瘤中独立地重新表达。