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
- 来源:
- 关键词:AdultAutomobile DrivingBiologyBrainBrain NeoplasmsCD8-Positive T-LymphocytesCD8B1 geneCellsChemotherapy and/or radiationClinicalContralateralCorpus CallosumDiagnosisDiffuseDiseaseExcisionFunctional disorderGene ExpressionGene MutationGenesGlioblastomaGoalsHyperactivityImmuneImmune responseInfiltrationJournalsKnock-outKnowledgeLaboratoriesLinkMalignant - descriptorModelingMolecularMusNatureNeoplasm MetastasisNeuronsOperative Surgical ProceduresPathogenesisPlayPopulationPrimary Brain NeoplasmsPrimary NeoplasmRecurrenceRoleSiteSurvival RateTumor Cell Migrationaxon guidancebasebrain parenchymachemokine receptorclinical investigationcohortexcitatory neurongenetic manipulationhuman diseaseinhibitory neuronmigrationmortalitymouse modelneoplastic cellnovelnovel therapeutic interventionoverexpressionresponsesingle-cell RNA sequencingtranscriptomicstumortumorigenesiswhite matter
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.
概括
胶质母细胞瘤(GBM)是成人原发性脑肿瘤的最常见和致命形式。一个特征
使其难以治愈的GBM是其在整个大脑中的扩散浸润,作为治疗
包括原发性肿瘤的手术切除总是会导致复发,通常远离
原始肿瘤。该临床特征说明了GBM生物学的关键知识差距,作为细胞和
驱动大脑肿瘤细胞迁移的分子机制仍然很差。最近的
研究表明,GBM进展与神经元活性密切相关,我们的初步研究表明
增加神经元活性会刺激GBM细胞向多动神经元的迁移
对侧半球。破译分子机制驱动活性依赖性GBM浸润,
我们对这些肿瘤进行了转录组分析,发现了轴突引导基因的富集和剧烈的
免疫相关签名的改变。用轴突引导基因组的功能研究表明,
小鼠GBM中EPHA6,EPHA7或SEMA4F的过表达促进了肿瘤细胞和
肿瘤轴承小鼠的存活率降低。同样,我们发现响应于活性的CD8-TCELLS降低
驱动的浸润和初步研究表明,这些人群的丧失会增强恶性
进展。
根据这些初步研究的优势,我们提出了三个试图发现的特定目标
驱动GBM浸润的细胞和分子机制。在AIM 1中,我们将操纵
神经元的子集为了剖析哪些亚类型神经元促进GBM浸润。在AIM2中,我们将
确定EPHA6,EPHA7和SEMA4F如何有助于GBM浸润和病理生理学。在AIM3中,我们
将确定神经元活性如何影响免疫反应,同时确定CD8 T细胞的方式
有助于GBM浸润。这些目的共同发现了哪些神经元种群促进GBM
浸润,同时揭示了轴突引导基因和趋化因子受体的新作用
病理生理学。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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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:
$ 45.44万 - 项目类别:
Systematic Characterization and Targeting of Neomorphic Drivers in Cancer
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- 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
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10736436 - 财政年份:2023
- 资助金额:
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Defining Astrocyte Engram Ensembles During Memory Formation
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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
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- 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
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10708356 - 财政年份:2021
- 资助金额:
$ 45.44万 - 项目类别:
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