Glial cell differentiation and glioma formation

胶质细胞分化和胶质瘤形成

• 批准号: 6607488
• 负责人: MARILYN D RESH
• 金额: $ 35.74万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-05 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6607488
• 关键词: biological signal transduction; carcinogenesis; cell differentiation; cell growth regulation; clinical research; cyclin dependent kinase; enzyme inhibitors; genetically modified animals; glia; glioma; green fluorescent proteins; growth inhibitors; guanine nucleotide binding protein; human subject; image processing; laboratory mouse; platelet derived growth factor; protooncogene; retinoblastoma protein; tissue /cell culture; tumor promoters

The overall goal of the proposed research is to elucidate the molecular mechanisms responsible for glial cell differentiation and to exploit the signaling components involved in differentiation as tools for the ultimate treatment of low grade gliomas. Previous work by our group established that autocrine loop PDGF signaling causes a dedifferentiation of astrocytes to glial progenitors in culture, and formation of low- grade gliomas in mice. Pharmacologic blockade of PDGF receptor tyrosine kinase activity causes the cells to revert to differentiated astrocyte-like cells. We therefore hypothesize that agents that are known to promote differentiation will reverse the tumorigenic phenotype. Our studies in primary oligodendrocytes have identified key signaling proteins, including Fyn, p190RhoGAP, Rho, and Cdk inhibitors, that are involved in oligodendrocyte differentiation. We therefore intend to directly test the ability of these signaling molecules to regulate glial cell differentiation in culture, and oligodendroglioma formation in mice and humans, as follows: Aim 1: To determine the role of Src family kinases, the Rho pathway, Cdk inhibitors and Rb family members in glial cell differentiation in culture. GFAP-PDGF as well as nestin-PDGF expressing cells will be infected with RCAS vectors encoding wt and mutant forms of Fyn, p190RhoGAP, Rho, p21 and p27 and the effects on growth and differentiation of the cells will be determined. Aim 2: To determine the role of Src family kinases, the Rho pathway, Cdk inhibitors and Rb family members in oligodendroglioma formation in vivo. Transgenic mice will be utilized to determine the role of the above molecules in tumor formation in mice. Aim 3: To analyze human oligodendrogliomas for activity of the above molecules and pathways in order to validate the proposed experimental models. The activity of the above proteins in human glioma tumor samples will be determined.

该研究的总体目标是阐明神经胶质细胞分化的分子机制，并利用参与分化的信号成分作为最终治疗低级别神经胶质瘤的工具。 我们小组之前的工作证实，自分泌环PDGF信号传导导致星形胶质细胞去分化为培养物中的神经胶质祖细胞，并在小鼠中形成低级别神经胶质瘤。 PDGF受体酪氨酸激酶活性的药理学阻断导致细胞恢复为分化的星形胶质细胞样细胞。 因此，我们假设已知促进分化的药物将逆转致瘤表型。 我们对原代少突胶质细胞的研究已经确定了参与少突胶质细胞分化的关键信号蛋白，包括 Fyn、p190RhoGAP、Rho 和 Cdk 抑制剂。 因此，我们打算直接测试这些信号分子在培养物中调节神经胶质细胞分化以及小鼠和人类少突胶质细胞瘤形成的能力，如下所示： 目标 1：确定 Src 家族激酶、Rho 通路、Cdk 抑制剂和Rb 家族成员在培养物中神经胶质细胞分化中的作用。 将用编码wt和突变形式的Fyn、p190RhoGAP、Rho、p21和p27的RCAS载体感染GFAP-PDGF以及巢蛋白-PDGF表达细胞，并确定对细胞生长和分化的影响。目标 2：确定 Src 家族激酶、Rho 通路、Cdk 抑制剂和 Rb 家族成员在体内少突胶质细胞瘤形成中的作用。 将利用转基因小鼠来确定上述分子在小鼠肿瘤形成中的作用。目标 3：分析人类少突神经胶质瘤的上述分子和通路的活性，以验证所提出的实验模型。 将测定人神经胶质瘤样品中上述蛋白质的活性。