Epigenetic pathways and cell cycle exit

表观遗传途径和细胞周期退出

基本信息

批准号：
10031091
负责人：
NAGI G AYAD
金额：
$ 36.07万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10031091
关键词：
Activity Cycles Affect Ataxia Behavioral Binding Biology Brain Breeding Cell Cycle Cell Cycle Progression Cell Proliferation Cells Cerebellar Ataxia Cerebellum Childhood Brain Neoplasm Chromatin Clinical Trials Cognitive deficits Cytoplasmic Granules Defect Development Down-Regulation Epigenetic Process Essential Genes Gene Expression Growth In Vitro Knock-out Knockout Mice Malignant Childhood Neoplasm Malignant Neoplasms Mus N-terminal Neuronal Differentiation Neurons Operative Surgical Procedures Pathway interactions Patients Phosphorylation Phosphotransferases Plague Process Proliferating Proteins Reader Regulation Resistance Role SHH gene Series Signal Pathway Sonic Hedgehog Pathway Testing Time Transcript Up-Regulation Work casein kinase casein kinase II chemotherapy clinical development gain of function granule cell in vivo inhibitor/antagonist insight medulloblastoma mouse model mutant nerve stem cell novel therapeutics progenitor small molecule standard of care stem cell proliferation stem cells transcriptome sequencing tumor growth upstream kinase

项目摘要

PROPOSAL SUMMARY Medulloblastoma is the most common pediatric brain tumor. Although some forms of medulloblastoma are treatable by surgery and chemotherapy, others are resistant to the standard of care. In addition, behavioral and cognitive deficits plague many medulloblastoma patients. Therefore, new therapeutic options are needed for treating medulloblastoma. Inhibitors of the epigenetic reader protein Brd4 are currently being tried in medulloblastoma patients due to their potential ability to reduce drivers of medulloblastoma growth including MYC. However, the underlying biology of Brd4 in the developing brain is not understood. We have recently shown that Brd4 knockout during development leads to cerebellar ataxia. We also demonstrated that Brd4 regulation via phosphorylation occurs during cell cycle exit of cerebellar granule cell progenitors. However, the functional importance of this regulation is unclear. In the proposed studies we will determine whether Brd4 phosphorylation is part of a switch-like mechanism controlling cell proliferation and cell cycle exit in GCPs and whether dysregulation of this process contributes to medulloblastoma. In Aim 1, we will determine the Brd4 signaling pathways important for GCP cell cycle exit. In Aim 2 we will determine the role of two upstream kinases CK1d and CK2a in controlling Brd4 activity and cell cycle exit. In Aim 3, we will determine the consequence of modulating Brd4 levels and phosphorylation status on progression of mouse medulloblastoma. Collectively, these studies will reveal the importance of the epigenetic reader protein Brd4 in the decision to proliferate or exit the cell cycle, which is critical for regulated development.

提案摘要髓母细胞瘤是最常见的小儿脑肿瘤。尽管某些形式的髓母细胞瘤是可以通过手术和化学疗法治疗，其他人对护理标准有抵抗力。另外，行为认知缺陷困扰着许多髓母细胞瘤患者。因此，需要新的治疗选择用于治疗髓母细胞瘤。目前正在尝试使用表观遗传读取器蛋白BRD4的抑制剂髓母细胞瘤患者的潜在能力减少了髓母细胞瘤的驱动因素，包括妈妈。但是，尚不清楚发育中的大脑中BRD4的潜在生物学。我们最近有表明在发育过程中，BRD4敲除导致小脑共济失调。我们还证明了BRD4 通过磷酸化调节是在小脑颗粒细胞祖细胞周期出口期间发生的。然而，该法规的功能重要性尚不清楚。在拟议的研究中，我们将确定BRD4是否磷酸化是控制细胞增殖和GCP中细胞周期出口的开关样机制的一部分，该过程的失调是否导致髓母细胞瘤。在AIM 1中，我们将确定BRD4 信号通路对于GCP细胞周期出口很重要。在AIM 2中，我们将确定两个上游的作用激酶CK1D和CK2A控制BRD4活性和细胞周期出口。在AIM 3中，我们将确定调节BRD4水平和磷酸化状态对小鼠髓母细胞瘤进展的结果。总的来说，这些研究将揭示表观遗传学读取器蛋白BRD4的重要性。扩散或退出细胞周期，这对于调节发育至关重要。