MOLECULAR DISSECTION OF SEIZURE MICROENVIRONMENT IN MALIGNANT GLIOMA

恶性胶质瘤癫痫微环境的分子解剖

基本信息

  • 批准号:
    10062889
  • 负责人:
  • 金额:
    $ 63.21万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-12-15 至 2022-11-30
  • 项目状态:
    已结题

项目摘要

Glioblastoma cells trigger pharmacoresistant seizures that may promote tumor growth and diminish the quality of remaining life. To define the relationship between growth of glial tumors and their neuronal microenvironment, and to identify genomic biomarkers and mechanisms that may point to better prognosis and treatment of drug resistant epilepsy in brain cancer, we are analyzing a new generation of genetically defined CRISPR/in utero electroporation inborn glioblastoma (GBM) tumor models engineered in mice. The molecular pathophysiology of glioblastoma cells and surrounding neurons and untransformed astrocytes will be compared at serial stages of tumor development in three genetic mouse strains: wild type, seizure prone, and seizure resistant. Preliminary data reveal that epileptiform EEG spiking is a very early and reliable preclinical signature of GBM expansion preceding other neurological deficits in these mice, followed by rapidly progressive seizures and death within weeks. Transcriptomic analysis of cortical astrocytes reveals the expansion of a subgroup enriched in pro-synaptogenic genes that may drive hyperexcitability, a novel mechanism of epileptogenesis. In Specific Aim 1 we will systematically define the earliest appearance of cortical hyperexcitability in wild type mice with a prototypical GBM and correlate its progression with in vivo and neuropathological imaging of invasive tumor cell location, in vitro electrophysiology, and molecular markers of key epilepsy pathogenic cascades in peritumoral neurons, including impaired glutamate reuptake, altered GABA gated-chloride gradients, and synaptic densities. In Specific Aim 2 we will correlate these findings with detailed FACS-sorted transcriptomic profiles of both transformed and wild type astrocytes in the peritumoral region to test the novel hypothesis that peritumoral hyperexcitability is driven in part by astrocytic subtypes that disrupt synaptic E/I homeostasis. In Specific Aim 3, we will use this benchmark approach in WT brain to compare growth, electrophysiological and molecular pathological profiles of the same tumor generated in a hyperexcitable brain bearing a single gene deletion (Kcna1) that dramatically lowers the threshold for seizures and shortens lifespan, and in a monogenic deletion strain (MapT/tau) that raises cortical seizure threshold and prolongs life, in order to examine the contribution of host neuronal excitability to tumor expansion. Our approach sets the stage to broadly explore the developmental biology of personalized tumor/host interactions in mice engineered with novel human tumor mutations in specified glial cell lineages.
胶质母细胞瘤细胞触发药物抗癫痫发作,可能促进肿瘤生长并降低质量 剩下的生活。定义神经胶质肿瘤的生长与神经元之间的关系 微环境,并确定基因组生物标志物和机制,这些机制可能表明预后更好, 治疗脑癌中耐药性癫痫的治疗,我们正在分析新一代的遗传定义 CRISPR/子宫电穿孔中的天生胶质母细胞瘤(GBM)肿瘤模型在小鼠中设计。分子 胶质母细胞瘤细胞以及周围神经元和未转化的星形胶质细胞的病理生理学将是 在三种遗传小鼠菌株中肿瘤发育的串行阶段进行了比较:野生型,癫痫发作和 抗癫痫发作。初步数据表明,癫痫样EEG尖峰是一个非常早期可靠的临床前 在这些小鼠中其他神经系统缺陷之前的GBM扩展的签名,然后迅速 几周之内进行性癫痫发作和死亡。皮质星形胶质细胞的转录组分析揭示了 富含突触的基因的亚组的扩展,可能驱动过度兴奋性,一种新型 癫痫发生的机理。在特定目标1中,我们将系统地定义最早的外观 具有原型GBM的野生型小鼠的皮质过度刺激性,并将其进展与体内和体内和 浸润性肿瘤细胞位置,体外电生理学和分子标记的神经病理学成像 周围神经元中关键的癫痫病致病性级联反应,包括谷氨酸再摄取,改变了 GABA门控氯化物梯度和突触密度。在特定目标2中,我们将将这些发现与 详细的FACS分类的转化和野生类型星形胶质细胞的转录组轮廓图 检验新的假设的区域,即周围过度兴奋性是由星形胶质细胞亚型驱动的 破坏突触E/I稳态。在特定目标3中,我们将使用这种基准方法在wt大脑中 比较A中同一肿瘤的生长,电生理和分子病理特征 过度可见的大脑带有单个基因缺失(KCNA1),该基因删除极大地降低了癫痫发作的阈值 并缩短寿命,并在单一的缺失菌株(MAPT/TAU)中提高皮质癫痫发作阈值和 延长寿命,以检查宿主神经元兴奋性对肿瘤扩张的贡献。我们的 方法为广泛探索个性化肿瘤/宿主互动的发育生物学设定了舞台 在特定的神经胶质细胞谱系中用新型人类肿瘤突变设计的小鼠中。

项目成果

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Benjamin Deneen其他文献

Benjamin Deneen的其他文献

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{{ truncateString('Benjamin Deneen', 18)}}的其他基金

Astrocyte Transcriptional Dependencies in Brain Circuits
脑回路中星形胶质细胞的转录依赖性
  • 批准号:
    10665221
  • 财政年份:
    2023
  • 资助金额:
    $ 63.21万
  • 项目类别:
Systematic Characterization and Targeting of Neomorphic Drivers in Cancer
癌症新形态驱动因素的系统表征和靶向
  • 批准号:
    10717973
  • 财政年份:
    2023
  • 资助金额:
    $ 63.21万
  • 项目类别:
Transcriptional Regulation in ZFTA-RELA Ependymoma
ZFTA-RELA 室管膜瘤的转录调控
  • 批准号:
    10736436
  • 财政年份:
    2023
  • 资助金额:
    $ 63.21万
  • 项目类别:
Defining Astrocyte Engram Ensembles During Memory Formation
定义记忆形成过程中的星形胶质细胞印迹整体
  • 批准号:
    10722056
  • 财政年份:
    2023
  • 资助金额:
    $ 63.21万
  • 项目类别:
Cellular and Molecular Mechanisms of GBM Infiltration
GBM 浸润的细胞和分子机制
  • 批准号:
    10583559
  • 财政年份:
    2022
  • 资助金额:
    $ 63.21万
  • 项目类别:
Cellular and Molecular Mechanisms of GBM Infiltration
GBM 浸润的细胞和分子机制
  • 批准号:
    10383061
  • 财政年份:
    2022
  • 资助金额:
    $ 63.21万
  • 项目类别:
MOLECULAR AND CELLULAR CONTROL OF INJURY-INDUCED ASTROGENESIS
损伤引起的星形细胞生成的分子和细胞控制
  • 批准号:
    10335708
  • 财政年份:
    2021
  • 资助金额:
    $ 63.21万
  • 项目类别:
Defining Roles for Astrocyte Subpopulations in the Aging Brain
定义星形胶质细胞亚群在衰老大脑中的作用
  • 批准号:
    10192033
  • 财政年份:
    2021
  • 资助金额:
    $ 63.21万
  • 项目类别:
Defining Roles for Astrocyte Subpopulations in the Aging Brain
定义星形胶质细胞亚群在衰老大脑中的作用
  • 批准号:
    10581539
  • 财政年份:
    2021
  • 资助金额:
    $ 63.21万
  • 项目类别:
Defining Roles for Astrocyte Subpopulations in the Aging Brain
定义星形胶质细胞亚群在衰老大脑中的作用
  • 批准号:
    10390425
  • 财政年份:
    2021
  • 资助金额:
    $ 63.21万
  • 项目类别:

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A Phase 2 biomarker driven, Study of DB107, a Retroviral Replicating Vector, Combined With 5-FC in Patients with Recurrent Glioblastoma or Anaplastic Astrocytoma
由生物标志物驱动的 DB107(一种逆转录病毒复制载体)与 5-FC 联合治疗复发性胶质母细胞瘤或间变性星形细胞瘤患者的 2 期研究
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Harvard/Stanford GTN Program: Novel targeted therapeutics for glioblastoma
哈佛/斯坦福 GTN 项目:胶质母细胞瘤的新型靶向疗法
  • 批准号:
    10306226
  • 财政年份:
    2021
  • 资助金额:
    $ 63.21万
  • 项目类别:
Harvard/Stanford GTN Program: Novel targeted therapeutics for glioblastoma
哈佛/斯坦福 GTN 项目:胶质母细胞瘤的新型靶向疗法
  • 批准号:
    10491787
  • 财政年份:
    2021
  • 资助金额:
    $ 63.21万
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Novel Approaches to Modeling and Treating IDH1 Mutant Glioma
IDH1 突变神经胶质瘤建模和治疗的新方法
  • 批准号:
    10004011
  • 财政年份:
    2019
  • 资助金额:
    $ 63.21万
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Novel Approaches to Modeling and Treating IDH1 Mutant Glioma
IDH1 突变神经胶质瘤建模和治疗的新方法
  • 批准号:
    10247533
  • 财政年份:
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  • 资助金额:
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