Modeling gliomagenesis with aging glial progenitor cells and hosts

描述(由申请人提供)：人脑胶质瘤的发病率在65岁到85岁之间最高，因此是一种老年性疾病。尽管积极努力设计新的治疗方法，恶性胶质瘤仍然迅速和一致地致命，特别是在老年人口中。改善胶质瘤患者预后的一个主要障碍是，目前基于应用于发育中动物的致癌范例的临床前动物模型未能预测人类的治疗效果。我们的初步研究表明，正常成人脑和胶质瘤中的大多数增殖细胞具有共同的胶质前体细胞(GPC)免疫表型。由于人类胶质瘤是一种衰老疾病，这一发现支持了衰老的胶质前体细胞(A-GPC)可能是人类胶质瘤形成的靶点的观点。尤其重要的是，围产期GPC的生物学表型，在现有模型中更多地以此为靶点，与终生持续的成人GPC明显不同。因此，老年脑GPC是一种更具相关性的脑胶质瘤靶细胞，可用于模拟人类疾病。尽管人类胶质瘤具有与年龄相关的临床特征，年轻和老年神经胶质前体细胞具有不同的生物学表型，而且随着年龄的增长，基因组的不稳定性增加，但衰老靶细胞在胶质瘤形成中的作用从未被讨论过。这种忽视在一定程度上反映了老年神经前体细胞特有的实验挑战，与年轻的神经前体细胞相比，这些细胞在体外不那么丰富、增殖，更容易衰老。与R21机制的意图一致，这一探索性建议涉及开发以前未探索的范式来转变老化的成人GPC(A-GPC)的重大挑战。我们的中心假设是，与年轻的靶细胞和宿主相比，靶细胞和宿主大脑微环境的老化相互作用将重现人类疾病，并产生不同的肿瘤表型。这项建议的目的是：1)比较围产期、青壮年和老年GPC的肿瘤易感性和表型；2)表征和比较这些转化的GPC在围产期、青壮年和老年脑中产生的动物胶质瘤的表型。这一合作项目的意义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老化对体内形成的胶质瘤表型的影响，该项目涉及胶质瘤生物学、干细胞和祖细胞生物学以及衰老方面的专家。这些研究将为未来的R01提案提供基础，以便更全面地分析衰老对胶质瘤表型的影响机制，并确立将衰老纳入胶质瘤治疗前临床试验的相对优点。

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.