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.

摘要