Chronic versus acute effects of p53 deletion on Olig2 progenitor malignancy

p53 缺失对 Olig2 祖细胞恶性肿瘤的慢性与急性影响

• 批准号: 8384516
• 负责人: ROBERT C ROSTOMILY
• 金额: $ 8.65万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384516
• 关键词: Accounting; Acute; Address; Adult; Affect; Age; Aging; Animal Model; Biological Assay; Biological Models; Brain; CDKN2A gene; Cell physiology; Cells; Chronic; DNA; Data; Development; Down-Regulation; Engineering; Exposure to; Future; Genomic Instability; Glioma; Gliomagenesis; Human; Hypoxia; In Vitro; Incidence; Intrinsic factor; Link; Little' s Disease; Longevity; Malignant - descriptor; Malignant Neoplasms; Modeling; Molecular; Mus; Mutation; Neurobiology; Outcome; Pathogenesis; Patients; Population; Pre-Clinical Model; Prognostic Factor; Property; Reagent; Reporting; Research; Residual state; Resistance; Risk; System; Tamoxifen; Testing; Time; Tumor Suppressor Proteins; Validation; age effect; age related; aged; animal model development; base; follow-up; implantation; in vivo; innovation; malignant phenotype; malignant state; mouse model; nerve stem cell; nervous system disorder; novel; progenitor; recombinase; tool; treatment response; tumor

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. PUBLIC HEALTH RELEVANCE: Although patient age is arguably the most robust factor for survival glioma, the mechanisms underlying the negative impact of increased age on treatment responses and malignancy are completely unknown. Since p53, the central regulator of DNA integrity, is markedly decreased in aged neural progenitor cells (cells of glioma origin), we hypothesize that decreased p53 with age results in increased mutations and higher degree of tumor malignancy. Using a new mouse model where p53 can be eliminated from neural progenitor cells we will definitively confirm our hypothesis, provide new tools to model gliomas and facilitate future discovery of new treatments that account for the impact of aging on tumor malignancy and treatment resistance.

描述（由申请人提供）：人类神经胶质瘤几乎是一种致命的疾病，25 年来，结果几乎没有改善。尽管衰老可以说是神经胶质瘤风险、生存、恶性肿瘤和治疗抵抗的最重要的预后因素，但衰老尚未被纳入常规临床前模型中，并且导致衰老负面影响的潜在机制尚不清楚。在这里，我们建议跟进我们之前的新观察，即小鼠模型中的神经胶质瘤恶性肿瘤主要取决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p53活性随着神经祖细胞（NPC）衰老而慢性下降，与基因组不稳定性增加相关，可能部分解释了这种效应。因此，我们建议开发一种新型小鼠模型系统，在暴露于他莫昔芬后，p53可以从表达Olig2的NPC中暂时删除。这将允许明确确定慢性与急性 p53 缺失如何影响 Olig2 NPC（假定的胶质瘤细胞起源）的恶性潜力以及对基因组不稳定性的相关影响。我们希望证明这种多功能模型系统将有助于验证我们的假设，即随着衰老而发生的 p53 功能的慢性丧失会增强 NPC 的基因组不稳定性和恶性潜力。与R03机制保持一致，这些独立研究的完成将为神经生物学和神经系统疾病许多领域的普遍重要的未来研究提供有价值的新研究工具和数据。 公共卫生相关性：尽管患者年龄可以说是神经胶质瘤生存的最重要因素，但年龄增加对治疗反应和恶性肿瘤产生负面影响的机制尚不清楚。由于 p53（DNA 完整性的中央调节因子）在衰老的神经祖细胞（神经胶质瘤来源的细胞）中显着减少，因此我们推测 p53 随着年龄的增长而减少会导致突变增加和肿瘤恶性程度升高。使用可以从神经祖细胞中消除 p53 的新小鼠模型，我们将明确证实我们的假设，提供神经胶质瘤模型的新工具，并促进未来发现新的治疗方法，以解释衰老对肿瘤恶性肿瘤和治疗耐药性的影响。