Shared mechanisms of astrocyte maturation in development and glioblastoma

星形胶质细胞成熟与胶质母细胞瘤的共同机制

• 批准号: 10656525
• 负责人: Steven A Sloan
• 金额: $ 39.47万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656525
• 关键词: 3-Dimensional; ATAC-seq; Acceleration; Address; Adult; Affect; Astrocytes; Attenuated; Automobile Driving; Biological; Biological Assay; Biological Models; Brain; Cells; ChIP-seq; Characteristics; Chromatin; DNA Binding; Data; Development; Educational process of instructing; Engineering; Excision; Exhibits; Fetal Development; Genetic Transcription; Genomics; Glioblastoma; Gliomagenesis; Growth; Heterogeneity; Human; Human Development; In Vitro; Individual; Knock-out; Literature; Malignant Neoplasms; Maps; Modeling; Molecular; Mutation; Neuroglia; Neurons; Nuclear; Operative Surgical Procedures; Organoids; Phagocytosis; Population; Primary Brain Neoplasms; Process; Proliferating; Protocols documentation; Scheme; Severity of illness; Shapes; System; Testing; Work; candidate identification; cell behavior; cell type; curative treatments; driver mutation; epigenomics; experimental study; fetal; induced pluripotent stem cell; malignant neurologic neoplasms; neoplastic cell; novel; overexpression; postnatal human; progenitor; programs; stem cells; temporal measurement; therapy resistant; three dimensional cell culture; transcription factor; transcriptome sequencing; transcriptomics; tumor

Project Summary Glioblastoma (GBM) is the most common and deadliest primary brain tumor in adults. Recent work continues to support the idea that this cancer (like many others) echoes the proliferation and differentiation programs from earlier developmental stages. The possibility that neurological cancers like GBM are essentially `locked in' to a developmental program and retain the controls that instruct these cell populations during development opens new and exciting opportunities. Furthermore, it places an emphasis on the need to identify the molecular triggers that govern the transition of immature progenitor cells to quiescent mature astrocytes during development. In this project we will test the hypothesis that master transcriptional regulators are sufficient for driving astrocyte maturation and that these factors can be used to jump-start stalled maturation within GBM-astrocytes. The ability of individual or small groups of transcription factors to drive cell fate or maturation changes has been demonstrated in a variety of cell types, including neurons and glia. To begin, we used existing transcriptomic, epigenomic, and DNA-binding data to identify a targeted set of candidate transcription factors that we hypothesize catalyze the astrocyte maturation process. We will test whether these transcription factors are capable of inducing precocious maturation in immature human astrocytes by manipulating their expression using schemes that mirror their developmental activity. As a model system, we are using human iPSC-derived cortical organoids, which provides a multicellular platform in which astrogenesis and maturation occurs endogenously along a timescale analogous to what is observed in the fetal and early postnatal human brain. We will also ask how the developmental trajectory of astrocyte maturation is perturbed in the setting of GBM by comparing epigenomic profiles of maturing human astrocytes from the organoid system with single cell data from surgical GBM resections. This comparison will place GBM-astrocyte differentiation in the context of the normal developmental trajectory and reveal potential transcription factors whose absence may contribute to stalled maturation. An important possibility in the pathobiology of gliomagenesis is that the heterogeneous mutations accumulated within GBM-astrocytes render them unreceptive to maturation-inducing transcription factors. Thus, in a final set of experiments, we will use isogenic iPSC lines harboring driver GBM mutations to test their influence on the receptivity to maturation-inducing transcription factors. Together, these studies will help teach us how and where GBM cells are stalled in their developmental programs and offer novel avenues to pursue differentiation schemes to mitigate these deadly tumors.

项目摘要 胶质母细胞瘤（GBM）是成年人中最常见，最致命的原发性脑肿瘤。最近的工作继续 支持这种癌症（与许多其他癌症）相呼应的观念 较早的发展阶段。像GBM这样的神经癌的可能性本质上是“锁定”到 开发计划并保留指导这些细胞群体在开发过程中的控件 新的令人兴奋的机会。此外，它重点是识别分子触发器的需求 在发育过程中，主要的祖细胞过渡到静止成熟的星形胶质细胞。 在这个项目中，我们将检验以下假设：主转录调节器足以驱动星形胶质细胞 成熟，这些因素可用于在GBM - 腹膜细胞中跳下衰落的成熟。能力 驱动细胞命运或成熟变化的单个或小组的转录因子是 以多种细胞类型的形式证明，包括神经元和神经胶质。首先，我们使用了现有的转录组， 表观基因组和DNA结合数据，以识别我们 假设催化星形胶质细胞的成熟过程。我们将测试这些转录因素是否是 能够通过使用其表达来诱导未成熟的人类星形胶质细胞的早熟 反映其发展活动的计划。作为模型系统，我们正在使用人类IPSC衍生的皮质 Organoids，提供了一个多细胞平台，在该平台中，天气生成和成熟发生了 沿着时间尺度类似于胎儿和产后人脑中观察到的时间。 我们还将询问星形胶质细胞成熟的发育轨迹如何在GBM的环境中扰动 比较器官系统的人类星形胶质细胞的表观基因组谱与单细胞数据 手术GBM切除术。此比较将在正常情况下将GBM - 胃细胞分化放置 发育轨迹和揭示潜在的转录因子，其缺失可能导致失速 成熟。神经胶质作用的病理生物学的重要可能性是异质突变 积累在GBM - 腹膜细胞中，使它们对诱导成熟的转录因子的启发性不受控制。因此， 在最后一组实验中，我们将使用带有驱动器GBM突变的等源性IPSC线来测试其影响 关于诱导成熟的转录因子的接受度。这些研究将有助于我们教会我们的方式和 GBM细胞在其发展计划中停滞不前的地方，并提供新的途径来追求差异化 减轻这些致命肿瘤的方案。