Identification and targeting of mechanisms specific to glioma stem cells in glioblastoma

胶质母细胞瘤中胶质瘤干细胞特异性机制的鉴定和靶向

基本信息

  • 批准号:
    10434100
  • 负责人:
  • 金额:
    $ 35.57万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-08-15 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract Glioblastoma (GBM) is the most common and most malignant primary brain tumor and has a dismal prognosis. Abundant evidence now indicates that a small subset of neoplastic cells, referred to as Glioma Stem Cells (GSCs), governs biologic behavior and resistance to therapy. GSCs inhabit specific biologic niches and have properties of self-renewal, pluripotency and high tumorigenicity. They can be identified by expression of markers, such as CD133, CD15 and nestin, yet molecular mechanisms responsible for their specific stem-like behavior in glioblastomas have not been fully defined. This proposal aims to define mechanisms underlying fundamental biological properties of GSCs, including: 1) their marked accumulation following the development of necrosis and tendency to localize to the hypoxic niche; and 2) a disrupted program of asymmetric cell division that favors self-renewing division over differentiation. We have developed novel in vitro and in vivo models and analytic techniques to study the differential behavior of stem and non-stem glioma cells within the tumor micro-environment, especially as it relates to their accumulation in regions of hypoxia. These include an in vivo orthotopic xenograft model in which stem cells are interrogated for patterns and mechanisms of accumulation following the induction of necrosis using a photo-activated dye. We also dissect pathways that direct asymmetric cellular division in Drosophila nervous system provide clues to understand the stem/non-stem dynamics in malignant gliomas. We have previously demonstrated that the human ortholog of Drosophila Brat, Trim3, is a tumor suppressor that regulates glioma stem cell dynamics and promotes stemness when lost. Here we propose to investigate novel regulatory mechanisms that arise during transition to the stem cell phenotype that can be antagonized therapeutically. Regulatory networks and potential therapeutic targets are further explored in xenografts and genetically engineered mouse models that recapitulates human gliomas to show efficacy.
项目总结/文摘

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas.
  • DOI:
    10.1007/s00401-020-02127-9
  • 发表时间:
    2020-03
  • 期刊:
  • 影响因子:
    12.7
  • 作者:
    Brat DJ;Aldape K;Colman H;Figrarella-Branger D;Fuller GN;Giannini C;Holland EC;Jenkins RB;Kleinschmidt-DeMasters B;Komori T;Kros JM;Louis DN;McLean C;Perry A;Reifenberger G;Sarkar C;Stupp R;van den Bent MJ;von Deimling A;Weller M
  • 通讯作者:
    Weller M
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DANIEL J BRAT其他文献

DANIEL J BRAT的其他文献

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{{ truncateString('DANIEL J BRAT', 18)}}的其他基金

Modeling the Glioblastoma Microenvironment to Uncover Progression Mechanisms and Therapeutic Targets
模拟胶质母细胞瘤微环境以揭示进展机制和治疗靶点
  • 批准号:
    10394722
  • 财政年份:
    2020
  • 资助金额:
    $ 35.57万
  • 项目类别:
Modeling the Glioblastoma Microenvironment to Uncover Progression Mechanisms and Therapeutic Targets
模拟胶质母细胞瘤微环境以揭示进展机制和治疗靶点
  • 批准号:
    10611990
  • 财政年份:
    2020
  • 资助金额:
    $ 35.57万
  • 项目类别:
Identification and targeting of mechanisms specific to glioma stem cells in glioblastoma
胶质母细胞瘤中胶质瘤干细胞特异性机制的鉴定和靶向
  • 批准号:
    9756347
  • 财政年份:
    2018
  • 资助金额:
    $ 35.57万
  • 项目类别:
Identification and targeting of mechanisms specific to glioma stem cells in glioblastoma
胶质母细胞瘤中胶质瘤干细胞特异性机制的鉴定和靶向
  • 批准号:
    9978761
  • 财政年份:
    2018
  • 资助金额:
    $ 35.57万
  • 项目类别:
Identification and targeting of mechanisms specific to glioma stem cells in glioblastoma
胶质母细胞瘤中胶质瘤干细胞特异性机制的鉴定和靶向
  • 批准号:
    10212336
  • 财政年份:
    2018
  • 资助金额:
    $ 35.57万
  • 项目类别:
Molecular Target Variation Across Environments and at Margins of Glioblastoma
不同环境和胶质母细胞瘤边缘的分子靶标变化
  • 批准号:
    8675210
  • 财政年份:
    2013
  • 资助金额:
    $ 35.57万
  • 项目类别:
Molecular Target Variation Across Environments and at Margins of Glioblastoma
不同环境和胶质母细胞瘤边缘的分子靶标变化
  • 批准号:
    9634560
  • 财政年份:
    2013
  • 资助金额:
    $ 35.57万
  • 项目类别:
Molecular Target Variation Across Environments and at Margins of Glioblastoma
不同环境和胶质母细胞瘤边缘的分子靶标变化
  • 批准号:
    9063107
  • 财政年份:
    2013
  • 资助金额:
    $ 35.57万
  • 项目类别:
Molecular Target Variation Across Environments and at Margins of Glioblastoma
不同环境和胶质母细胞瘤边缘的分子靶标变化
  • 批准号:
    8502036
  • 财政年份:
    2013
  • 资助金额:
    $ 35.57万
  • 项目类别:
CANCER TISSUE AND PATHOLOGY SHARED RESOURCE
癌症组织和病理学共享资源
  • 批准号:
    8512147
  • 财政年份:
    2012
  • 资助金额:
    $ 35.57万
  • 项目类别:
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