Epigenetic pathways and cell cycle exit

提案摘要 髓母细胞瘤是最常见的小儿脑肿瘤。虽然某些形式的髓母细胞瘤是 可通过手术和化疗治疗，其他人则对标准治疗有抵抗力。此外，行为 和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阅读蛋白Brd4的抑制剂目前正在试验中。 髓母细胞瘤患者，因为他们的潜在能力，以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潜在生物学尚不清楚。我们最近 显示发育过程中Brd4敲除导致小脑共济失调。我们还证明了Brd4 通过磷酸化的调节发生在小脑颗粒祖细胞的细胞周期退出期间。然而，在这方面， 这项规定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GCP中细胞增殖和细胞周期退出的开关样机制的一部分， 这一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Brd 4 对GCP细胞周期退出重要的信号通路。在目标2中，我们将确定两个上游 激酶CK 1d和CK 2a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结果。 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，这对调控发育至关重要。

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.