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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结