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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：
Timothy Gershon
金额：
$ 34.23万
依托单位：
EMORY UNIVERSITY
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：
https://reporter.nih.gov/project-details/10837315
关键词：
Affect Animals Apoptosis Apoptotic Brain Brain Diseases Brain Neoplasms Cell Death Cell Death Induction Cell Survival Cells Cerebellum Childhood Brain Neoplasm Complex Congenital cerebellar hypoplasia Cytoplasmic Granules DNA DNA Damage DNA biosynthesis Development Exons Failure Finding by Cause Genes Genetic Genetic Screening Goals Grant Growth Heterogeneity Hour Human Impairment Individual Intervention Link Malignant neoplasm of brain Mediating Messenger RNA Microcephaly Mitosis Mitotic Molecular Mus Mutate Mutation Normal Cell Pathogenesis Pathology Pattern Pediatric Neoplasm Phenotype Play Population Process Proliferating Prosencephalon RNA Decay RNA Processing RNA Splicing Recurrence Recurrent tumor Regulation Resistance Role S phase System TP53 gene Testing Therapeutic Time animal breeding cancer therapy clinically relevant efficacy testing genome integrity improved in vivo insight medulloblastoma mind control mouse genetics mouse model mutant neoplastic cell nerve stem cell neurogenesis novel postnatal prevent progenitor replication stress response stem cells transcriptomics tumor tumor 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删除会导致 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，小鼠可以通过时间控制删除Magoh，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。