Energy Stress in Brain Tumor Initiating Stem Cells

脑肿瘤起始干细胞中的能量应激

基本信息

  • 批准号:
    8785788
  • 负责人:
  • 金额:
    $ 34.67万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-08-01 至 2019-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The human brain represents one of the most metabolically active organs with a highly efficient ability to extract glucose as the primary currency for energy and carbon source. In particular, neurons are distinguished in their ability to preferentially absorb glucose from a nutrient-restricted environment through the expression of high affinity glucose transporters. The most prevalent primary brain tumor, glioblastoma, ranks among the most lethal of human cancers. Like the normal brain, glioblastomas contain cellular hierarchies with self-renewing, multi-lineage cells at the apex. These brain tumor initiating cells display therapeutic resistance, promote tumor angiogenesis, and invade into normal tissues providing rationale to model their regulation and develop targeting strategies. We recently demonstrated that brain tumor initiating cells display a marked ability to survive the reduced nutrient levels found in the neoplastic brain through the cooption of the neuronal glucose transporter, GLUT3. In contrast, non-stem cell-like tumor cells underwent cell death with nutrient restriction with a cellular plasticity towards a stem cell-like state in surviving cells. Collectivly, these studies identify a novel molecular mechanism associated with the tumor cellular hierarchy that could provide a node of fragility as targeting GLUT3 expression reduced brain tumor initiating cell self-renewal and tumor growth. Like all cancers, glioblastomas display the Warburg effect, a preferential utilization of aerobic glycolysis for energy supplies. This aerobic glycolyss frees the cells from oxygen requirements and provides a steady supply of anabolic material yet is highly glucose inefficient and requires a steady supply of glucose, suggesting a potential therapeutic target. Based on this background, we hypothesize that preferential glucose uptake shields brain tumor initiating cells from extracellular energy stress and provides an ability to these cells to occupy a diverse set of niches with different metabolic limitations. The anti-angiogenic bevacizumab has shown promise in the initial response of tumors to therapy but has failed to extend survival. Studies have suggested that angiogenic inhibitor resistance is associated with impaired vascular function and metabolic shifts that may enrich for tumor initiating cells. To investigate these potential links between cellular metabolism and the tumor hierarchy, we will dissect the interplay between brain tumor initiating cells and the tumor microenvironment. In the first aim, we will determine the role of the stem cell metabolic responses in stress resistance. In the second aim, we will interrogate the role of glucose uptake in different tumor microenvironments enriched in tumor initiating cells through the use of regional biopsies from human patients and regionally specific Glut3 modification in animal studies. Finally, we will investigate the potential synthetic lethality of targeting GLUT3 with bevacizumab or ketogenic diet therapy. We will employ a series of models derived from human glioblastomas and epilepsy tissues to lay the foundation for advanced modeling of this lethal brain disease.
描述(由申请人提供):人脑是代谢最活跃的器官之一,具有高效提取葡萄糖作为能量和碳源的主要货币的能力。特别是,神经元在它们的能力上是有区别的

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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JEREMY N RICH其他文献

JEREMY N RICH的其他文献

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{{ truncateString('JEREMY N RICH', 18)}}的其他基金

Dynamic Complexity of Brain Tumor Stem Cells (R35CA197718)
脑肿瘤干细胞的动态复杂性 (R35CA197718)
  • 批准号:
    10419906
  • 财政年份:
    2021
  • 资助金额:
    $ 34.67万
  • 项目类别:
Dual Targeting of Brain Tumor Initiating Cells through Inhibition of BMI1 and EZH2
通过抑制 BMI1 和 EZH2 双重靶向脑肿瘤起始细胞
  • 批准号:
    9981829
  • 财政年份:
    2017
  • 资助金额:
    $ 34.67万
  • 项目类别:
Dual Targeting of Brain Tumor Initiating Cells through Inhibition of BMI1 and EZH2 (R01NS103434)
通过抑制 BMI1 和 EZH2 双重靶向脑肿瘤起始细胞 (R01NS103434)
  • 批准号:
    10450285
  • 财政年份:
    2017
  • 资助金额:
    $ 34.67万
  • 项目类别:
Dual Targeting of Brain Tumor Initiating Cells through Inhibition of BMI1 and EZH2
通过抑制 BMI1 和 EZH2 双重靶向脑肿瘤起始细胞
  • 批准号:
    9398480
  • 财政年份:
    2017
  • 资助金额:
    $ 34.67万
  • 项目类别:
Dual Targeting of Brain Tumor Initiating Cells through Inhibition of BMI1 and EZH2 (R01NS103434)
通过抑制 BMI1 和 EZH2 双重靶向脑肿瘤起始细胞 (R01NS103434)
  • 批准号:
    10201765
  • 财政年份:
    2017
  • 资助金额:
    $ 34.67万
  • 项目类别:
Dynamic Complexity of Brain Tumor Stem Cells
脑肿瘤干细胞的动态复杂性
  • 批准号:
    9325306
  • 财政年份:
    2015
  • 资助金额:
    $ 34.67万
  • 项目类别:
Dynamic Complexity of Brain Tumor Stem Cells
脑肿瘤干细胞的动态复杂性
  • 批准号:
    9767056
  • 财政年份:
    2015
  • 资助金额:
    $ 34.67万
  • 项目类别:
Dynamic Complexity of Brain Tumor Stem Cells
脑肿瘤干细胞的动态复杂性
  • 批准号:
    8955796
  • 财政年份:
    2015
  • 资助金额:
    $ 34.67万
  • 项目类别:
Dynamic Complexity of Brain Tumor Stem Cells
脑肿瘤干细胞的动态复杂性
  • 批准号:
    9117541
  • 财政年份:
    2015
  • 资助金额:
    $ 34.67万
  • 项目类别:
Instructive Cues in Glioblastoma Hierarchies
胶质母细胞瘤层次结构中的指导性线索
  • 批准号:
    8786649
  • 财政年份:
    2014
  • 资助金额:
    $ 34.67万
  • 项目类别:

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