IGSF3 promotes tumor progression through synaptic remodeling and hyperexcitability in malignant glioma
IGSF3通过恶性神经胶质瘤的突触重塑和过度兴奋促进肿瘤进展
基本信息
- 批准号:10315147
- 负责人:
- 金额:$ 4.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-01 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAutomobile DrivingBackBar CodesBehaviorBindingBinding ProteinsBioinformaticsBiological AssayBiological ProcessBrainBrain NeoplasmsBromodeoxyuridineCRISPR/Cas technologyCancer BiologyCell CommunicationCell CycleCellsCo-ImmunoprecipitationsComplexDataDevelopmentDevelopmental BiologyDiagnosisDiseaseDisease ProgressionElectroencephalographyElectrophysiology (science)ElectroporationExcitatory SynapseFeedsGenesGlioblastomaGliomaGoalsGrowthHematoxylin and Eosin Staining MethodHistopathologyHumanImmunofluorescence ImmunologicImmunoglobulinsImpairmentIn SituIn VitroInhibitory SynapseInvestigationLaboratoriesLeadMaintenanceMalignant - descriptorMalignant GliomaMalignant NeoplasmsMalignant neoplasm of brainMalignant neoplasm of central nervous systemMapsMass Spectrum AnalysisMembraneMembrane ProteinsMethodologyModelingMonitorMorphogenesisMusNeuroepithelial, Perineurial, and Schwann Cell NeoplasmNeuronsNeurosciencesOncogenesOncogenicOperative Surgical ProceduresPathway interactionsPatientsPlayPotassiumPotassium ChannelProteomicsRadiation therapyReportingResearchResearch ProposalsRoleSamplingScientific InquirySeizuresSideSignal PathwaySliceSourceStructureSurvival RateSynapsesTechniquesTestingTissue MicroarrayTransposaseTreatment ProtocolsTumor BiologyTumor TissueVariantanticancer researchbaseearly onsetexperimental studyfetalgain of functionglioma cell linein uteroin vivoinnovationloss of functionmembermigrationmouse modelneoplastic cellneurodevelopmentneuronal circuitrynovelnovel therapeutic interventionoverexpressionpostnatalpostsynapticpreservationpresynapticprogramssurvival outcomesynaptogenesistranscriptome sequencingtranscriptomicstumortumor progression
项目摘要
PROJECT SUMMARY
Malignant gliomas are a group of high-grade brain neoplasms that represent the most common form of
malignant brain tumors. Current treatment regimens include an amalgamation of surgical, chemotherapeutic
and radiation treatments yet median survival for the most lethal glioma variant, glioblastoma multiforme (GBM)
remains stagnant at a mere 15 months post-diagnosis. While new scientific inquiries continue to yield novel
disease-driving mechanisms, survival rates have remained unchanged over the past 30 years, highlighting a
need for new therapeutic approaches for these uniformly fatal diseases.
The existence of developmental paradigms in cancer biology has long been established as a source of
dysregulated biological processes that facilitate tumor progression. In addition to developmental biology
approaches in cancer research, recent scientific investigations have revealed that malignant gliomas form
direct synaptic electrochemical connections with extratumoral neurons in order to sustain continued
proliferation and migration. The study of this complex interplay between glioma cells and non-tumor neural
cells has launched a new line of scientific inquiry known as “cancer neuroscience”. Given the existence of both
of these developmental and neuroscientific precedents, we propose to investigate how developmental
programs responsible for synaptogenesis and synaptic maintenance are utilized and sustained in malignant
glioma.
Our laboratory has identified a novel membrane-bound protein, immunoglobulin superfamily member 3
(IGSF3), with high expression levels in both in utero neurodevelopment and malignant glioma. Previous
studies have shown that IGSF3 controls neuronal morphogenesis in the developing brain and our preliminary
data suggests it may serve as a novel fetal oncogene with markedly increased expression in both development
and malignant glioma but minimal expression in the postnatal brain. Our preliminary studies using an in utero
electroporation mouse model of glioma have revealed that IGSF3 overexpression drives tumor progression by
increasing proliferation and decreasing survival. Furthermore, overexpression of IGSF3 promotes early-onset
seizures in tumor mice and selectively increases excitatory presynaptic and postsynaptic components at the
tumor margin. Based on our initial studies, we have hypothesized that increased IGSF3 drives progression of
malignant glioma by disrupting the synaptic microenvironment and increasing hyperexcitability in the
surrounding neuronal circuitry. This hyperexcitability then feeds back to the tumor to promote tumor
progression through increased mitogenic and promigratory signaling pathways. Herein, our research proposal
seeks to summarize previously reported research findings and our preliminary experimental results that
support our hypothesis and rationale, and aims to explain the significance and innovation of our study as well
as the scientific methodologies and techniques we will utilize in order to execute our lines of scientific inquiry.
项目概要
恶性胶质瘤是一组高级别脑肿瘤,代表最常见的形式
恶性脑肿瘤。目前的治疗方案包括手术、化疗相结合
和放射治疗,但最致命的胶质瘤变异——多形性胶质母细胞瘤(GBM)的中位生存期
诊断后仅 15 个月仍处于停滞状态。虽然新的科学探究不断产生新颖的成果
疾病驱动机制,生存率在过去 30 年中保持不变,突显了
需要新的治疗方法来治疗这些致命的疾病。
癌症生物学中发展范式的存在早已被确立为
失调的生物过程促进肿瘤进展。除了发育生物学
癌症研究方法,最近的科学研究表明,恶性胶质瘤形成
与肿瘤外神经元的直接突触电化学连接,以维持持续的
扩散和迁移。神经胶质瘤细胞与非肿瘤神经细胞之间复杂相互作用的研究
细胞启动了一条新的科学探究路线,称为“癌症神经科学”。鉴于两者的存在
在这些发育和神经科学先例中,我们建议研究发育如何
负责突触发生和突触维持的程序在恶性疾病中得到利用和维持
神经胶质瘤。
我们的实验室鉴定出一种新型膜结合蛋白,免疫球蛋白超家族成员3
(IGSF3),在子宫神经发育和恶性神经胶质瘤中都有高表达水平。以前的
研究表明 IGSF3 控制发育中大脑的神经元形态发生,我们的初步研究表明
数据表明它可能作为一种新的胎儿癌基因,在发育和发育过程中表达显着增加
和恶性神经胶质瘤,但在出生后大脑中表达极少。我们的初步研究使用子宫内
神经胶质瘤的电穿孔小鼠模型表明,IGSF3 过表达通过以下方式驱动肿瘤进展:
增加增殖并降低存活率。此外,IGSF3的过度表达促进早发
肿瘤小鼠的癫痫发作并选择性地增加兴奋性突触前和突触后成分
肿瘤边缘。根据我们的初步研究,我们假设 IGSF3 的增加会导致疾病进展
恶性神经胶质瘤通过破坏突触微环境并增加神经元的过度兴奋性
周围的神经元电路。这种过度兴奋然后反馈给肿瘤,促进肿瘤生长
通过增加有丝分裂和前迁移信号通路来进展。在此,我们的研究计划
旨在总结之前报道的研究结果和我们的初步实验结果
支持我们的假设和基本原理,并旨在解释我们研究的意义和创新
作为我们用来执行科学探究的科学方法和技术。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Rachel Naomi Curry其他文献
Rachel Naomi Curry的其他文献
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