Chronic versus acute effects of p53 deletion on Olig2 progenitor malignancy

描述（由申请人提供）：人类胶质瘤是一种几乎一致致命的疾病，在过去的25年里几乎没有改善。尽管衰老可以说是胶质瘤风险、生存、恶性和治疗抵抗的最重要的预后因素，但它尚未被纳入常规的临床前模型，而且导致衰老负面影响的潜在机制尚不清楚。在这里，我们建议继续我们先前的新观察，即小鼠模型中的胶质瘤恶性肿瘤主要依赖于与年龄相关的细胞内在因素。在潜在的候选机制中，我们发现神经祖细胞（npc）中p53活性随衰老的慢性下降，与基因组不稳定性增加有关，可能部分解释了这种效应。因此，我们建议开发一种新的小鼠模型系统，在暴露于他莫昔芬后，p53可以暂时从表达Olig2的npc中删除。这将允许明确地确定慢性和急性p53缺失如何影响Olig2 NPCs（假定的胶质瘤细胞起源）的恶性潜能以及对基因组不稳定性的相关影响。我们希望证明这个多功能模型系统将有助于验证我们的假设，即p53功能的慢性丧失，随着年龄的增长，增加了npc的基因组不稳定性和恶性潜能。与R03机制保持一致，这些独立研究的完成将为未来在神经生物学和神经系统疾病的许多领域具有普遍重要性的研究提供有价值的新研究工具和数据。

DESCRIPTION (provided by applicant): Human gliomas are a nearly uniformly fatal disease and little improvement in outcome has been realized in over 25 years. Although arguably the most important prognostic factor for glioma risk, survival, malignancy and treatment resistance, aging has not been incorporated into routine pre-clinical models and the underlying mechanisms responsible for the negative effects of aging are not known. Here we propose to follow up on our previous novel observation that glioma malignancy in a mouse model is primarily dependent on age-related cell intrinsic factors. Among potential candidate mechanisms, we discovered that a chronic decline in p53 activity with aging in neural progenitor cells (NPCs), associated with increased genomic instability, may in part account for this effect. Therefore we propose to develop a novel mouse model system whereby p53 can be deleted from Olig2 expressing NPCs after exposure to tamoxifen in a temporal fashion. This will permit the unambiguous determination of how chronic versus acute p53 deletion affects the malignant potential of Olig2 NPCs (putative glioma cells of origin) and associated effects on genomic instability. We expect to demonstrate that this versatile model system will facilitate validation of our hypothesis that chronic loss of p53 function, as occurs with aging, enhances genomic instability and malignant potential in NPCs. In keeping with the R03 mechanism, the completion of these self-contained studies will provide valuable new research tools and data for future studies of general importance in many fields of neurobiology and nervous system disease.