Cellular and Molecular Mechanisms of GBM Infiltration

GBM 浸润的细胞和分子机制

基本信息

  • 批准号:
    10383061
  • 负责人:
  • 金额:
    $ 45.44万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-03-15 至 2027-02-28
  • 项目状态:
    未结题

项目摘要

Summary Glioblastoma (GBM) is the most common and deadly form of primary brain tumor in adults. One feature of GBM that makes it exceedingly difficult to cure is its diffuse infiltration throughout the brain, as treatment, including surgical resection of the primary tumor invariably results in recurrence, often remote from the site of the original tumor. This clinical feature illustrates a key knowledge gap in GBM biology, as the cellular and molecular mechanisms that drive the migration of tumor cells in the brain remain poorly defined. Recent studies have shown that GBM progression is tightly linked to neuronal activity and our preliminary studies show that increased neuronal activity stimulates migration of GBM cells towards hyperactive neurons in the contralateral hemisphere. To decipher the molecular mechanisms driving activity-dependent, GBM infiltration, we performed transcriptomic analysis of these tumors, finding enrichment of axon guidance genes and drastic alterations in immune-related signatures. Functional studies with the axon guidance gene cohort revealed that overexpression of EphA6, EphA7, or Sema4F in mouse GBM promoted infiltration of tumor cells and decreased survival of tumor bearing mice. Similarly, we found decreased CD8-Tcells in response to activity- driven infiltration and preliminary studies suggest that loss of these populations enhances malignant progression. Based on the strength of these preliminary studies we propose three specific aims that seek to uncover the cellular and molecular mechanisms driving GBM infiltration. In aim 1, we will manipulate the activity of subsets of neurons in order to dissect which sub-types of neurons promote GBM infiltration. In aim2, we will determine how EphA6, EphA7, and Sema4F contribute to GBM infiltration and pathophysiology. In aim3, we will determine how neuronal activity influences immune responses, while determining how CD8 T-cells contribute to GBM infiltration. Together, these aims will uncover which neuronal populations promote GBM infiltration, while revealing new roles for axon guidance genes and chemokine receptors in tumor pathophysiology.
总结 胶质母细胞瘤(GBM)是成人中最常见和最致命的原发性脑肿瘤。的一个特征 GBM使其极难治愈的是其弥漫性浸润整个大脑,作为治疗, 包括手术切除原发性肿瘤总是会导致复发,通常远离肿瘤的部位。 原来的肿瘤。这种临床特征说明了GBM生物学中的关键知识缺口,因为细胞和 驱动肿瘤细胞在脑中迁移的分子机制仍然不清楚。最近 研究表明,GBM进展与神经元活动密切相关,我们的初步研究表明, 增加的神经元活性刺激GBM细胞向过度活跃的神经元迁移, 对侧半球为了破译驱动活动依赖性GBM浸润的分子机制, 我们对这些肿瘤进行了转录组学分析,发现了轴突导向基因的富集, 免疫相关特征的改变。轴突导向基因组的功能研究显示, 小鼠GBM中EphA 6、EphA 7或Sema 4F的过表达促进肿瘤细胞的浸润, 降低荷瘤小鼠的存活率。同样地,我们发现CD 8-T细胞减少是对活动的反应, 驱动的浸润和初步研究表明,这些群体的损失增强了恶性肿瘤的发生。 进展 基于这些初步研究的优势,我们提出了三个具体目标,旨在揭示 驱动GBM浸润的细胞和分子机制。在目标1中,我们将操纵 为了剖析哪些神经元亚类促进GBM浸润,需要对神经元亚类进行分类。在aim 2中,我们将 确定EphA 6、EphA 7和Sema 4F如何促进GBM浸润和病理生理学。在aim 3中,我们 将确定神经元活动如何影响免疫反应,同时确定CD 8 T细胞 有助于GBM渗透。总之,这些目标将揭示哪些神经元群体促进GBM 同时揭示了轴突导向基因和趋化因子受体在肿瘤中的新作用 病理生理学

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Benjamin Deneen其他文献

Benjamin Deneen的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:
    $ 45.44万
  • 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:
    $ 45.44万
  • 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:
    $ 45.44万
  • 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:
    $ 45.44万
  • 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:
    $ 45.44万
  • 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:
    $ 45.44万
  • 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:
    $ 45.44万
  • 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:
    $ 45.44万
  • 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:
    $ 45.44万
  • 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:
    10708356
  • 财政年份:
    2021
  • 资助金额:
    $ 45.44万
  • 项目类别:

相似海外基金

Establishment of a method for evaluating automobile driving ability focusing on frontal lobe functions and its application to accident prediction
以额叶功能为中心的汽车驾驶能力评价方法的建立及其在事故预测中的应用
  • 批准号:
    20K07947
  • 财政年份:
    2020
  • 资助金额:
    $ 45.44万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Evaluation of the Effectiveness of Multi-Professional Collaborative Assessment of Cognitive Function and Automobile Driving Skills and Comprehensive Support
认知功能与汽车驾驶技能多专业协同评估效果评价及综合支持
  • 批准号:
    17K19824
  • 财政年份:
    2017
  • 资助金额:
    $ 45.44万
  • 项目类别:
    Grant-in-Aid for Challenging Research (Exploratory)
Development of Flexible Automobile Driving Interface for Disabled People
残疾人灵活汽车驾驶界面开发
  • 批准号:
    25330237
  • 财政年份:
    2013
  • 资助金额:
    $ 45.44万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Automobile driving among older people with dementia: the effect of an intervention using a support manual for family caregivers
患有痴呆症的老年人的汽车驾驶:使用家庭护理人员支持手册进行干预的效果
  • 批准号:
    23591741
  • 财政年份:
    2011
  • 资助金额:
    $ 45.44万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了