Defining the crucial role of MAGOH in cerebellar development and the potential for targeting the EJC in medulloblastoma treatment
定义 MAGOH 在小脑发育中的关键作用以及在髓母细胞瘤治疗中靶向 EJC 的潜力
基本信息
- 批准号:10837315
- 负责人:
- 金额:$ 34.23万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-15 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAnimalsApoptosisApoptoticBrainBrain DiseasesBrain NeoplasmsCell DeathCell Death InductionCell SurvivalCellsCerebellumChildhood Brain NeoplasmComplexCongenital cerebellar hypoplasiaCytoplasmic GranulesDNADNA DamageDNA biosynthesisDevelopmentExonsFailureFinding by CauseGenesGeneticGenetic ScreeningGoalsGrantGrowthHeterogeneityHourHumanImpairmentIndividualInterventionLinkMalignant neoplasm of brainMediatingMessenger RNAMicrocephalyMitosisMitoticMolecularMusMutateMutationNormal CellPathogenesisPathologyPatternPediatric NeoplasmPhenotypePlayPopulationProcessProliferatingProsencephalonRNA DecayRNA ProcessingRNA SplicingRecurrenceRecurrent tumorRegulationResistanceRoleS phaseSystemTP53 geneTestingTherapeuticTimeanimal breedingcancer therapyclinically relevantefficacy testinggenome integrityimprovedin vivoinsightmedulloblastomamind controlmouse geneticsmouse modelmutantneoplastic cellnerve stem cellneurogenesisnovelpostnatalpreventprogenitorreplication stressresponsestem cellstranscriptomicstumortumor growth
项目摘要
ABSTRACT
We propose to study the role of the exon junction complex (EJC) in cerebellar development and medulloblastoma.
Medulloblastoma is the most common malignant brain tumor in children, and it arises as a disruption of postnatal
cerebellar neurogenesis. We have found that neural progenitors in the postnatal cerebellum strictly require EJC function,
as genetic deletion of the EJC component Magoh induces catastrophic DNA damage and cell death specifically in these
cells. We developed mice in which Magoh could be deleted with temporal control, and found that Magoh deletion causes
cell death throughout the cerebellar progenitor population within 72 hours. Moreover, we raised medulloblastoma-prone
mice in which Magoh could be deleted with temporal control and found the Magoh deletion in tumors caused DNA
damage and cell death similar to the effect in progenitor cells. Based on these findings, we propose that the EJC plays a
central, previously unappreciated role in maintaining the genomic integrity and the survival of cerebellar progenitors and
medulloblastoma cells. Uncovering the mechanisms through which the EJC regulates progenitors and medulloblastoma
cells will provide new insight into the pathogenesis of brain growth failure in microcephaly and may lead to new
treatments for medulloblastoma. Aim 1 of the grant will focus on cerebellar progenitors and use Magoh deletion to
identify the mechanisms of DNA integrity and cell survival that depend on the EJC. Aim 2 will use Magoh deletion to
determine how EJC disruption alters tumor growth in a primary, in vivo mouse model of medulloblastoma. These Aims
will show how the EJC maintains progenitor survival during brain growth and test the hypothesis that the EJC can be
targeted to improve medulloblastoma therapy.
摘要
我们建议研究外显子连接复合体(EJC)在小脑发育和髓母细胞瘤中的作用。
髓母细胞瘤是儿童最常见的恶性脑肿瘤,
小脑神经发生我们已经发现,出生后小脑中的神经祖细胞严格需要EJC功能,
由于EJC组分的基因缺失,Magoh诱导了灾难性的DNA损伤和细胞死亡,特别是在这些细胞中,
细胞我们开发了可以通过时间控制删除Magoh的小鼠,并发现Magoh缺失导致
72小时内整个小脑祖细胞群的细胞死亡。此外,我们提出了髓母细胞瘤倾向,
小鼠,其中Magoh可以与时间控制删除,并发现肿瘤中的Magoh缺失导致DNA
损伤和细胞死亡类似于祖细胞中的效果。基于这些发现,我们认为EJC发挥着
在维持小脑祖细胞的基因组完整性和存活方面,
髓母细胞瘤细胞揭示EJC调节祖细胞和髓母细胞瘤的机制
细胞将提供新的见解脑生长障碍的发病机制,在小头畸形,并可能导致新的
治疗髓母细胞瘤该补助金的目标1将集中在小脑祖细胞上,并使用Magoh缺失来
确定依赖于EJC的DNA完整性和细胞存活的机制。目标2将使用Magoh删除,
确定EJC破坏如何改变髓母细胞瘤的原发性体内小鼠模型中的肿瘤生长。这些目标
将显示EJC如何在大脑生长过程中维持祖细胞存活,并测试EJC可以
旨在改善髓母细胞瘤治疗。
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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Timothy Gershon其他文献
Timothy Gershon的其他文献
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{{ truncateString('Timothy Gershon', 18)}}的其他基金
Bcl-xL-regulated apoptosis in cerebellar development and medulloblastoma treatment
Bcl-xL 调节小脑发育和髓母细胞瘤治疗中的细胞凋亡
- 批准号:
10462482 - 财政年份:2018
- 资助金额:
$ 34.23万 - 项目类别:
Bcl-xL-regulated apoptosis in cerebellar development and medulloblastoma treatment
Bcl-xL 调节小脑发育和髓母细胞瘤治疗中的细胞凋亡
- 批准号:
9923746 - 财政年份:2018
- 资助金额:
$ 34.23万 - 项目类别:
Defining the crucial role of MAGOH in cerebellar development and the potential for targeting the EJC in medulloblastoma treatment
定义 MAGOH 在小脑发育中的关键作用以及在髓母细胞瘤治疗中靶向 EJC 的潜力
- 批准号:
10199065 - 财政年份:2018
- 资助金额:
$ 34.23万 - 项目类别:
Bcl-xL-regulated apoptosis in cerebellar development and medulloblastoma treatment
Bcl-xL 调节小脑发育和髓母细胞瘤治疗中的细胞凋亡
- 批准号:
10906483 - 财政年份:2018
- 资助金额:
$ 34.23万 - 项目类别:
Glycolytic regulation of cerebellar development and medulloblastoma tumorigenesis
小脑发育和髓母细胞瘤肿瘤发生的糖酵解调节
- 批准号:
9012118 - 财政年份:2015
- 资助金额:
$ 34.23万 - 项目类别:
Aerobic glycolysis regulates apoptosis in neurogenesis and medulloblastoma
有氧糖酵解调节神经发生和髓母细胞瘤中的细胞凋亡
- 批准号:
8641442 - 财政年份:2012
- 资助金额:
$ 34.23万 - 项目类别:
Aerobic glycolysis regulates apoptosis in neurogenesis and medulloblastoma
有氧糖酵解调节神经发生和髓母细胞瘤中的细胞凋亡
- 批准号:
8433510 - 财政年份:2012
- 资助金额:
$ 34.23万 - 项目类别:
Aerobic glycolysis regulates apoptosis in neurogenesis and medulloblastoma
有氧糖酵解调节神经发生和髓母细胞瘤中的细胞凋亡
- 批准号:
8828814 - 财政年份:2012
- 资助金额:
$ 34.23万 - 项目类别:
Aerobic glycolysis regulates apoptosis in neurogenesis and medulloblastoma
有氧糖酵解调节神经发生和髓母细胞瘤中的细胞凋亡
- 批准号:
8276734 - 财政年份:2012
- 资助金额:
$ 34.23万 - 项目类别:
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