Targeting mechanisms of medulloblastoma formation
髓母细胞瘤形成的靶向机制
基本信息
- 批准号:9213395
- 负责人:
- 金额:$ 38.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-07-01 至 2021-06-30
- 项目状态:已结题
- 来源:
- 关键词:Abnormal CellAdhesionsAngiogenesis InhibitorsAnimal ModelBAI1 geneBAI2 geneBAI3 geneBrainCellsCentral Nervous System NeoplasmsCerebellumCessation of lifeChildCytoplasmic GranulesDNA-Binding ProteinsDataDevelopmentDiseaseEZH2 geneEnsureEpigenetic ProcessFamilyFamily memberGenesGliomaGrowthHistonesHumanIntellectual functioning disabilityKnockout MiceKnowledgeLaboratoriesLeadLinkLysineMBD2 proteinMalignant NeoplasmsMalignant neoplasm of brainMalignant neoplasm of central nervous systemMalignant neoplasm of lungMalignant neoplasm of ovaryMediatingMethylationMolecularMorbidity - disease rateMusNeoplastic Cell TransformationNeuraxisNeurobiologyNeurologicOperative Surgical ProceduresOrphanOutcomePathway interactionsPatientsPhysically HandicappedPhysiologicalPredispositionProcessPropertyRadiation therapyReagentResearchRoleSecondary toSignal PathwaySignal TransductionSolidSomatic MutationSurvival RateSystems DevelopmentTP53 geneTertiary Protein StructureTestingTherapeuticTherapeutic EffectThickTimeTransgenic MiceTumor SuppressionTumor Suppressor ProteinsTumorigenicityVertebral columnbasecell growthchemotherapydevelopmental neurobiologydisabilitydosagedrug candidateexperiencegene functionhistone methyltransferaseimprovedin vivoinnovationirradiationmalignant breast neoplasmmedulloblastomamouse modelneuron developmentneuronal tumornew therapeutic targetnovelnovel therapeutic interventionnovel therapeuticsoverexpressionpostnatalpromoterpublic health relevancerestorationseven-transmembrane G-protein-coupled receptorsmall moleculesmall molecule inhibitortherapeutic targettumortumor growthtumorigenesistumorigenic
项目摘要
DESCRIPTION (provided by applicant): There is an urgent need to develop novel therapies for patients with medulloblastoma (MB), the most common malignant central nervous system (CNS) tumor in children. Current treatments include surgery, radiotherapy, and chemotherapy and result in 5-year survival rates of 40-90% depending on subtype. Moreover, children suffer important morbidity secondary to treatment, including neurological, intellectual and physical disabilities. The overall purpose of the present project is to investigate the role of the Brain-specific Angiogenesis Inhibitor 1 (BAI1) in cerebellar development and susceptibility to transformation, and explore new therapies for MB based on the related mechanisms. BAI1 is an orphan seven transmembrane G protein-coupled receptor (GPCR) specifically expressed in the brain, and belonging to the adhesion-type sub-family. Our new preliminary data show that BAI1 expression is significantly reduced in patients with MBs, and the promoter is epigenetically silenced, suggesting that BAI1 loss may facilitate MB formation. To test this in the physiological setting, we generated Bai1 knockout (KO) mice and found haploinsufficiency of Bai1 dramatically accelerates MB tumorigenesis in Ptch1+/- transgenic mouse models of MB, the first demonstration that a reduction in Bai1 dosage can promote MB formation in vivo. Interestingly, we detected enhanced Gli1/2 expression and a thicker external granule layer (EGL) during early postnatal cerebellum development in the Bai1 KO mice. Therefore, our preliminary studies link BAI1 with cerebellar development and neoplastic transformation. Based on these results, we hypothesize that BAI1 is a tumor suppressor in the cerebellum and that restoration of its expression with epigenetic therapy may represent a novel therapeutic intervention for MB. To test our hypothesis, we propose the following aims: (i) determine whether Bai1 loss accelerates MB formation in mice through abnormal activation of a growth-signaling pathway in the developing cerebellum, (ii) determine how BAI1 restoration in human MB cells can inhibit their growth, and alter their tumorigenic properties, and (iii) define the mechanisms of BAI1 inactivation in MB, and determine whether epigenetic reactivation of BAI1 expression has therapeutic effects in vivo. These studies are important as they increase our knowledge about developmental neurobiology in the CNS, and may lead to the development of novel therapeutic approaches for patients with medulloblastoma.
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)
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ERWIN G VAN MEIR其他文献
ERWIN G VAN MEIR的其他文献
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{{ truncateString('ERWIN G VAN MEIR', 18)}}的其他基金
Mechanisms underlying BAI1/ADGRB1 negative regulation of glioblastoma mesenchymal transition and invasion.
BAI1/ADGRB1 胶质母细胞瘤间质转化和侵袭负调控的机制。
- 批准号:
10034438 - 财政年份:2021
- 资助金额:
$ 38.65万 - 项目类别:
Mechanisms underlying BAI1/ADGRB1 negative regulation of glioblastoma mesenchymal transition and invasion.
BAI1/ADGRB1 胶质母细胞瘤间质转化和侵袭负调控的机制。
- 批准号:
10687227 - 财政年份:2021
- 资助金额:
$ 38.65万 - 项目类别:
Mechanisms underlying BAI1/ADGRB1 negative regulation of glioblastoma mesenchymal transition and invasion.
BAI1/ADGRB1 胶质母细胞瘤间质转化和侵袭负调控的机制。
- 批准号:
10488569 - 财政年份:2021
- 资助金额:
$ 38.65万 - 项目类别:
Targeting Mechanisms of Medulloblastoma Formation
髓母细胞瘤形成的靶向机制
- 批准号:
10179178 - 财政年份:2020
- 资助金额:
$ 38.65万 - 项目类别:
Evaluating ADGRB3 as a tumor suppressor epigenetically silenced in WNT medulloblastoma
评估 ADGRB3 作为 WNT 髓母细胞瘤中表观遗传沉默的肿瘤抑制因子
- 批准号:
9965891 - 财政年份:2019
- 资助金额:
$ 38.65万 - 项目类别:
Evaluating ADGRB3 as a tumor suppressor epigenetically silenced in WNT medulloblastoma
评估 ADGRB3 作为 WNT 髓母细胞瘤中表观遗传沉默的肿瘤抑制因子
- 批准号:
10358481 - 财政年份:2019
- 资助金额:
$ 38.65万 - 项目类别:
Evaluating ADGRB3 as a tumor suppressor epigenetically silenced in WNT medulloblastoma
评估 ADGRB3 作为 WNT 髓母细胞瘤中表观遗传沉默的肿瘤抑制因子
- 批准号:
10599504 - 财政年份:2019
- 资助金额:
$ 38.65万 - 项目类别:
Evaluating ADGRB3 as a tumor suppressor epigenetically silenced in WNT medulloblastoma
评估 ADGRB3 作为 WNT 髓母细胞瘤中表观遗传沉默的肿瘤抑制因子
- 批准号:
10057681 - 财政年份:2019
- 资助金额:
$ 38.65万 - 项目类别:
Evaluating ADGRB3 as a tumor suppressor epigenetically silenced in WNT medulloblastoma
评估 ADGRB3 作为 WNT 髓母细胞瘤中表观遗传沉默的肿瘤抑制因子
- 批准号:
10583473 - 财政年份:2019
- 资助金额:
$ 38.65万 - 项目类别:
Evaluating ADGRB3 as a tumor suppressor epigenetically silenced in WNT medulloblastoma
评估 ADGRB3 作为 WNT 髓母细胞瘤中表观遗传沉默的肿瘤抑制因子
- 批准号:
10738336 - 财政年份:2019
- 资助金额:
$ 38.65万 - 项目类别:
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