Epigenetic pathways and cell cycle exit

表观遗传途径和细胞周期退出

• 批准号: 10566978
• 负责人: NAGI G AYAD
• 金额: $ 36.07万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 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/10566978
• 关键词: Epigenetic; pathways; cell; cycle; exit

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儿童脑肿瘤。尽管某些形式的髓母细胞瘤 可以通过手术和化疗来治疗，其他人则对标准护理有抵抗力。此外，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。表观遗传读取蛋白 Brd4 的抑制剂目前正在试验中 髓母细胞瘤患者由于其潜在的能力来减少髓母细胞瘤生长的驱动因素，包括 MYC。然而，Brd4 在发育中的大脑中的基本生物学原理尚不清楚。我们最近有 表明发育过程中 Brd4 敲除会导致小脑共济失调。我们还证明了 Brd4 通过磷酸化的调节发生在小脑颗粒细胞祖细胞的细胞周期退出期间。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 GCP 中控制细胞增殖和细胞周期退出的开关样机制的一部分， 该过程的失调是否会导致髓母细胞瘤。在目标 1 中，我们将确定 Brd4 对 GCP 细胞周期退出很重要的信号通路。在目标 2 中，我们将确定两个上游的角色 激酶 CK1d 和 CK2a 控制 Brd4 活性和细胞周期退出。在目标 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影响。 总的来说，这些研究将揭示表观遗传阅读器蛋白 Brd4 在决定 增殖或退出细胞周期，这对于调节发育至关重要。