IGF SIGNAL TRANSDUCTION PATHWAY IN MEDULLOBLASTOMA
髓母细胞瘤中的 IGF 信号转导途径
基本信息
- 批准号:6825073
- 负责人:
- 金额:$ 25.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-09-30 至 2008-05-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Project #3: IGF-Signal Transduction Pathway in Medulloblastoma
A considerable line of evidence points at the IGF-I auto/paracrine system as an important component in the development and progression of brain tumors. Despite this, little attention has been paid to the role of IGF-I receptor (IGF-IR), and its signaling pathways, in primitive neuroectodermal tumors/ medulloblastomas (PNETs/MBs) that represent about 25% of all pediatric brain tumors. This research proposal is founded on the hypothesis that the IGF-IR system and the JCV T-antigen cooperate in the development and/or progression of medulloblastomas. Importance of this hypothesis is supported by several findings: (i) JC virus (JCV) infects greater than 80% of the human population; (ii) JCV T-antigen was found in human tumors including PNET/MBs; (iii) ectopic expression of JCV T-antigen transforms cells in culture and is tumorogenic in experimental animals; and (iv) JCV T-antigen, as well as, its murine counterpart - SV40 T-antigen, are not able to transform cells that do not possess functional IGF-IR. To further support our hypothesis, we have developed new evidence demonstrating
overexpression of the major IGF-IR substrate, IRS-1, in both human and mouse medulloblastoma cell lines, and the activation of IGF-I system including constitutive phosphorylation of the IGF-IR protein in biopsies from patients with medulloblastoma. We have also found that both JCV-T-antigen and IGF-IR are necessary for medulloblastoma cell lines to survive and grow in anchorage-independent culture condition, and finally, we have demonstrated that
JCV T-antigen and IRS-1 interact with each other. Three specific aims are proposed to directly test the hypothesis on the functional role for IGF-1 signaling pathway in the genesis of medulloblastoma; in the first aim mutational analysis of the IGF-IR will be utilized to determine whether functional interaction between the IGF-IR and JCV T-antigen contributes to malignant transformation in medulloblastomas; in the second aim JCV T-antigen positive and negative medulloblastoma cell lines will be employed to determine whether a unique set of IGF-IR pathways is involved in JCV T-antigen mediated transformation. Metabolic inhibitors in combination with mutational analysis of signaling molecules, including IRS-1 and PTEN phosphatase, will be employed to alter IGF-IR pathways and to test their importance in both T-antigen and non T-antigen mediated transformation; finally in the third aim dominant negative strategies against the IGF-IR and IRS-1 function will be tested in vivo. The results of these in
vivo studies will allow us to evaluate whether uncoupling of the IGF-IR signaling pathway/s from its functional synergy with JCV T-antigen will eliminate medulloblastoma tumors from cerebellar tissues.
项目#3:髓母细胞瘤的IGF信号转导途径
大量证据指向IGF-1自动/旁分泌系统是脑肿瘤发育和进展的重要组成部分。尽管如此,在原始神经外科肿瘤/髓母细胞瘤(PNETS/ MBS)中,IGF-I受体(IGF-IR)及其信号通路的作用几乎没有引起关注。该研究提案建立在以下假设的基础上:IGF-IR系统和JCV T抗原在髓母细胞瘤的发展和/或进展中合作。该假设的重要性得到了几个发现的支持:(i)JC病毒(JCV)感染了超过80%的人口; (ii)在包括PNET/MB在内的人类肿瘤中发现JCV T抗原; (iii)JCV T抗原的异位表达会转化培养物中的细胞,并且在实验动物中具有肿瘤性; (iv)JCV t-抗原以及其鼠类对应物-SV40 T-抗原,无法转化不具有功能性IGF-IR的细胞。为了进一步支持我们的假设,我们开发了新的证据证明
在人和小鼠髓母细胞瘤细胞系中,主要IGF-IR底物IRS-1的过表达以及IGF-I系统的激活,包括来自髓母细胞瘤患者的活检中IGF-IR蛋白的组成型磷酸化。我们还发现,JCV-T-抗原和IGF-IR对于髓母细胞瘤细胞系都是必要的
JCV T-抗原和IRS-1相互作用。提出了三个特定的目的,以直接检验髓母细胞瘤起源中IGF-1信号通路功能作用的假设。在第一个目标中,将利用对IGF-IR的突变分析来确定IGF-IR和JCV T抗原之间的功能相互作用是否有助于髓母细胞瘤中的恶性转化;在第二个目标中,JCV T抗原阳性和阴性髓母细胞瘤细胞系将用于确定JCV T抗原介导的转化是否涉及独特的IGF-IR途径。代谢抑制剂与包括IRS-1和PTEN磷酸酶在内的信号分子的突变分析相结合,用于改变IGF-IR途径,并测试其在T-抗原和非T-抗原介导的转化中的重要性;最后,在第三个目标中,针对IGF-IR和IRS-1功能的负面负面策略将在体内进行测试。这些结果
体内研究将使我们能够评估IGF-IR信号传导途径与JCV T抗原的功能协同作用是否会消除小脑组织中的髓母细胞瘤肿瘤。
项目成果
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数据更新时间:2024-06-01
Krzysztof Reiss的其他基金
New anti-glioblastoma metabolic compounds with high potential for Blood Brain Barrier penetration
新型抗胶质母细胞瘤代谢化合物具有穿透血脑屏障的巨大潜力
- 批准号:1054393110543931
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Center for Translational Viral Oncology (CTVO)
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Center for Translational Viral Oncology (CTVO)
转化病毒肿瘤学中心 (CTVO)
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- 财政年份:2017
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IGF induced neuronal protection and HIV-1 infection
IGF 诱导神经元保护和 HIV-1 感染
- 批准号:66726866672686
- 财政年份:2002
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IRS-1 - JC T-antigen Interaction in Cerebellar Tumors
IRS-1 - JC T 抗原在小脑肿瘤中的相互作用
- 批准号:70144817014481
- 财政年份:2002
- 资助金额:$ 25.98万$ 25.98万
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IRS-1 - JC T-antigen Interaction in Cerebellar Tumors
IRS-1 - JC T 抗原在小脑肿瘤中的相互作用
- 批准号:64648276464827
- 财政年份:2002
- 资助金额:$ 25.98万$ 25.98万
- 项目类别:
Nuclear IRS-1-DNA repair and mutagenesis in medulloblastoma
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- 批准号:75221817522181
- 财政年份:2002
- 资助金额:$ 25.98万$ 25.98万
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Nuclear IRS-1-DNA repair and mutagenesis in medulloblastoma
髓母细胞瘤中的核 IRS-1-DNA 修复和诱变
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IRS-1 - JC T 抗原在小脑肿瘤中的相互作用
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- 财政年份:2002
- 资助金额:$ 25.98万$ 25.98万
- 项目类别:
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