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.
项目总结
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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Rachel Naomi Curry其他文献
Rachel Naomi Curry的其他文献
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