Modeling gliomagenesis with aging glial progenitor cells and hosts

描述（由申请人提供）：人类胶质瘤在65至85岁之间发病率最高，因此是一种衰老疾病。尽管人们努力设计新的治疗方法，恶性神经胶质瘤仍然迅速而一致地致命，特别是在老年人中。改善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的动物的致癌范式，无法预测治疗在人类中的疗效。我们的初步研究表明，正常成人大脑和胶质瘤中的大多数增殖细胞具有共同的胶质祖细胞（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胶质祖细胞（a - gpcs）可能是人类胶质瘤形成的靶点的观点。特别重要的是，围产期GPC的生物学表型（在现有模型中更常见）与终生存在的成年GPC的生物学表型明显不同。因此，老年脑GPC是一种更适合模拟人类疾病的神经胶质瘤靶细胞。尽管人类胶质瘤的临床特征与年龄有关，年轻和衰老的胶质祖细胞具有不同的生物学表型，并且随着年龄的增长基因组不稳定性增加，但衰老靶细胞在胶质瘤形成中的作用从未得到解决。这种疏忽在一定程度上反映了衰老的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数量少，增殖能力差，更容易衰老。为了与R21机制的意图保持一致，该探索性提案涉及开发先前未被探索的范式来转化老化的成年GPCs （A-GPCs）的重大挑战。我们的中心假设是，与较年轻的靶点和宿主产生的肿瘤表型相比，衰老对靶细胞和宿主大脑微环境的相互作用将重现人类疾病，并产生不同的肿瘤表型。本提案的目的是：1)比较转化的围产期、青年和老年GPCs的肿瘤易感性和表型；2)表征和比较这些转化的GPCs在围产期、青年和老年大脑中产生的动物胶质瘤的表型。该合作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，其意义将是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R01提案提供基础，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的临床前测试的相对优势。

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.