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: 8529433
• 负责人: ROBERT C ROSTOMILY
• 金额: $ 8.22万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8529433
• 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.

描述（由申请人提供）：人类神经胶质瘤是一种几乎一致的致命性疾病，在过去25年中，几乎没有实现结局的改善。尽管可以说是胶质瘤风险、存活率、恶性程度和治疗抗性的最重要预后因素，但衰老尚未被纳入常规临床前模型，并且导致衰老负面影响的潜在机制尚不清楚。在这里，我们建议跟进我们以前的新的观察，神经胶质瘤恶性肿瘤的小鼠模型，主要是依赖于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活性随着衰老而慢性下降，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的小鼠模型系统，其中p53可以从Olig2表达NPC后，暴露于他莫昔芬在一个时间的方式删除。这将允许明确确定慢性与急性p53缺失如何影响Olig2 NPC（假定的神经胶质瘤细胞起源）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，这种多功能的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，增强基因组的不稳定性和恶性潜能的NPC。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未来研究提供有价值的新研究工具和数据。