Epigenetic pathways and cell cycle exit

表观遗传途径和细胞周期退出

• 批准号: 10227112
• 负责人: NAGI G AYAD
• 金额: --
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 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 2021-07-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227112
• 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

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.

建议书摘要 髓母细胞瘤是儿童最常见的脑肿瘤。尽管某些形式的髓母细胞瘤 其他人可以通过手术和化疗来治疗，但对护理标准有抵抗力。此外，行为 认知缺陷困扰着许多髓母细胞瘤患者。因此，需要新的治疗方案。 用于治疗髓母细胞瘤。表观遗传阅读器蛋白Brd4的抑制剂目前正在试验 髓母细胞瘤患者由于他们潜在的能力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还不清楚。我们最近做了 研究表明，发育过程中Brd4基因敲除会导致小脑性共济失调。我们还证明了Brd4 在小脑颗粒细胞前体细胞周期退出过程中，通过磷酸化进行调节。然而， 这一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 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 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Brd4 GCP细胞周期退出的重要信号通路。在目标2中，我们将确定两个上游 CK1d和CK2a在控制Brd4活性和细胞周期退出中的作用。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，这是调节发育的关键。