Modeling gliomagenesis with aging glial progenitor cells and hosts

描述（由申请人提供）：人类神经胶质瘤在65至85岁之间表现出最高的发病率，因此是一种衰老疾病。尽管在设计新疗法方面做出了大量努力，但恶性胶质瘤仍然是快速和一致的致命性，特别是在老年人群中。改善神经胶质瘤患者预后的一个主要障碍是目前临床前动物模型的失败，该模型基于应用于发育中动物的致癌范例，无法预测人类治疗的疗效。我们的初步研究表明，大多数增殖细胞在正常成人脑和胶质瘤共享一个共同的神经胶质祖细胞（GPC）的免疫表型。由于人脑胶质瘤是一种衰老性疾病，这一发现支持了衰老胶质祖细胞（A-GPCs）可能是人脑胶质瘤形成的靶点的观点。特别重要的是，围产期GPC的生物表型，更常见的目标在现有的模型中，是明显不同的成人GPC，持续整个生命。因此，来自老年脑的GPC是用于模拟人类疾病的更相关的胶质瘤靶细胞。尽管人类胶质瘤的年龄相关的临床概况，年轻和老化的胶质祖细胞的不同的生物学表型和随着年龄的增长基因组不稳定性的增加，老化的靶细胞在胶质瘤形成中的作用从未得到解决。这种疏忽部分反映了老年神经前体细胞所特有的实验挑战，这些细胞在体外比年轻的神经前体细胞更不丰富，增殖性更差，更容易衰老。为了与R21机制的意图保持一致，这个探索性的提议涉及开发以前未探索的范式来转化老化的成人GPCs（A-GPCs）的重大挑战。我们的中心假设是，靶细胞和宿主大脑微环境的衰老相互作用将重演人类疾病，并产生与年轻靶细胞和宿主产生的肿瘤表型不同的肿瘤表型。本提案的目的是i）比较转化的围产期、年轻成人和老年GPC的肿瘤易感性和表型，以及ii）表征和比较围产期、年轻成人和老年脑中由这些转化的GPC产生的动物胶质瘤的表型。这个合作项目的意义，涉及神经胶质瘤生物学，干细胞和祖细胞生物学和衰老方面的专家，将首次直接比较胶质瘤靶细胞和宿主脑微环境的发育阶段和衰老对体内形成的胶质瘤表型的影响。这些研究将为未来的R 01提案提供基础，以更全面地分析衰老对胶质瘤表型的作用机制，并确定将衰老纳入胶质瘤治疗临床前试验的相对优点。

DESCRIPTION (provided by applicant): Human gliomas exhibit their highest incidence between 65 and 85 years of life and hence are a disease of aging. Despite intensive effort to devise new therapies, malignant gliomas remain rapidly and uniformly fatal, particularly in the aged population. A major roadblock to improved outcome for patients with gliomas is the failure of current pre-clinical animal models, based on oncogenic paradigms applied to developing animals, to predict the efficacy of therapy in humans. Our preliminary studies demonstrated that the majority of proliferating cells in normal adult human brain and gliomas share a common glial progenitor cell (GPC) immunophenotype. Since human gliomas are a disease of aging, this finding supports the notion that aging glial progenitor cells (A-GPCs) are likely targets for human glioma formation. Of particular importance, the biological phenotype of the perinatal GPC, more commonly targeted in existing models, is distinctly different from that of the adult GPCs that persist throughout life. Therefore the GPC from aged brain is a more relevant glioma target cell to model the human disease. Despite the age-related clinical profile of human gliomas, the distinct biological phenotypes of young and aging glial progenitors and increased acquisition of genomic instability with age, the role of aging target cells in glioma formation has never been addressed. This oversight reflects, in part, the experimental challenges unique to aged neural precursor cells that are less abundant, proliferative and more prone to senescence in vitro than their young counterparts. In keeping with the intent of the R21 mechanism, this exploratory proposal involves the significant challenge of developing previously unexplored paradigms to transform aging adult GPCs (A-GPCs). Our central hypothesis is that the interactions of aging on target cells and the host brain microenvironment will recapitulate the human disease and produce distinct tumor phenotypes compared with those generated by younger targets and hosts. The objectives of this proposal are to i) compare the neoplastic vulnerability and phenotypes of transformed perinatal, young adult and aged GPCs and ii) to characterize and compare the phenotype of animal gliomas generated from these transformed GPCs in perinatal, young adult and aged brains. The significance of this collaborative project, involving experts in glioma biology, stem and progenitor cell biology and aging, will be for the first time to directly compare the impact of developmental stage and aging of both glioma target cells and host brain microenvironments on the glioma phenotype that forms in vivo. These studies will provide the basis for future R01 proposals to more comprehensively analyze the mechanism by which aging contributes to glioma phenotype and establish the relative merits of incorporating aging in pre-clinical testing of glioma therapies.