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
• 负责人: Timothy Gershon
• 金额: $ 33.65万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2022-06-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10199065
• 关键词: ASPM gene; Affect; Animals; Apoptosis; Apoptotic; Brain; Brain Diseases; Brain Neoplasms; Cell Death; Cell Survival; Cells; Cerebellum; Childhood Brain Neoplasm; Complex; Congenital cerebellar hypoplasia; Cytoplasmic Granules; DNA; DNA Damage; DNA biosynthesis; Development; Exons; Failure; Genes; Genetic; Genetic Screening; Goals; Grant; Growth; Heterogeneity; Hour; Human; Impairment; Individual; Intervention; Lead; 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; base; 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

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.

抽象的 我们建议研究外显子连接络合物（EJC）在小脑发育和髓母细胞瘤中的作用。 髓母细胞瘤是儿童中最常见的恶性脑肿瘤，它是由于产后的破坏而产生的 小脑神经发生。我们发现产后小脑中的神经祖细胞严格要求EJC功能， 由于EJC成分的遗传缺失MAGOH会诱导灾难性的DNA损伤和细胞死亡。 细胞。我们开发了可以通过时间控制删除Magoh的老鼠，发现Magoh删除原因 在72小时内，整个小脑祖细胞种群中的细胞死亡。此外，我们抚养了甲状腺母细胞瘤 可以通过时间控制删除magoH的小鼠，发现肿瘤中的magOH缺失引起DNA 损伤和细胞死亡类似于祖细胞的影响。基于这些发现，我们建议EJC扮演 中央，以前未批准的在维持基因组完整性和小脑祖细胞和生存的作用 髓母细胞瘤细胞。发现EJC调节祖细胞和髓母细胞瘤的机制 细胞将为小头畸形的大脑生长衰竭发病机理提供新的见解，并可能导致新的 髓母细胞瘤的治疗方法。赠款的目标1将重点放在小脑祖细胞上，并使用magoh删除 确定取决于EJC的DNA完整性和细胞存活的机制。 AIM 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小鼠模型中的肿瘤生长。这些目标 将显示EJC在大脑生长过程中如何保持祖细胞生存，并检验EJC可以是的假设 针对改善髓母细胞瘤疗法的目标。