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Investigating Pathophysiology of Glioma Stem Cells in 3D Bioprinted Vascularized Glioblastoma Model

研究 3D 生物打印血管化胶质母细胞瘤模型中胶质瘤干细胞的病理生理学

基本信息

批准号：
10373269
负责人：
Irtisha Singh
金额：
$ 21.85万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10373269
关键词：
3-Dimensional Ablation Adult Animal Model Area Astrocytes Biochemical Biocompatible Materials Biological Models Biology Biomedical Engineering Biophysics Blood Vessels Brain Brain Neoplasms Cell Differentiation process Cells Collaborations Cues Dependence Development Drug Screening Ecology Endothelial Cells Engineering Environment Epigenetic Process Equilibrium Exhibits Extracellular Matrix Failure Functional disorder Gene Expression Genetic Glioblastoma Glioma Goals Immune Immune system Implant In Vitro Letters Maintenance Malignant Neoplasms Modeling Molecular Molecular Genetics National Institute of Neurological Disorders and Stroke Nature Neoplasms in Vascular Tissue Normal Cell Organoids Pathologic Patients Pericytes Physiological Pre-Clinical Model Primary Brain Neoplasms Publications Radiation therapy Regulation Research Design Resistance Role Structure Survival Rate System Therapeutic Tissues bioink bioprinting body system cell type clinically relevant density design drug development high-throughput drug screening human disease in vitro Model in vivo innovation mouse model neoplastic cell nerve stem cell novel therapeutics patient derived xenograft model pre-clinical precision medicine programs relating to nervous system self-renewal stem cells stem-like cell stemness therapy development therapy resistant three-dimensional modeling tool tumor tumor growth tumor microenvironment tumorigenic

项目摘要

SUMMARY Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults with a 5-year survival rate of less than 5%. GBMs are highly vascular and lethal brain tumors that display cellular hierarchies containing self- renewing and radiotherapy resistant tumorigenic glioma stem cells (GSCs). Understanding of the molecular regulation of GSCs in its native environment is critical for drug development. The available in vitro models suffer from the momentous hurdle of lack of functional blood vessels. Vasculature is not only essential for keeping the tumor alive but also creating a tumor microenvironment that balances the dynamics of GSCs, enabling self-renewal and differentiation. Therefore, there is a significant need for a preclinical tumor model to investigate the progression and the therapeutic resistance nature of GBM tumor, and thereby aid in drug development for the treatment of GBM. The primary goal of this exploratory (R21) proposal is to (a) develop clinically-relevant bioengineered 3D vascularized GBM organoid models and (b) utilize them to interrogate GBM pathobiology. Specifically, 3D bioprinting approach will be used to design perfusable vascular networks with embedded GSC organoids in a brain-like extracellular matrix. This printed structure will have the potential to provide physiologically similar biophysical and biochemical microenvironment with perivascular niches to facilitate maintenance of stemness cues as well as transformation of GSCs into differentiated glioma cells. As ablation of GSCs represents a potential therapeutic approach for treatment of GBM, these bioengineered GBM models can be utilized to understand the molecular regulation of GSCs in a microenvironment mimicking its native surroundings. It is envisioned that these 3D bioprinted vascularized GBM models will not only serve as a powerful platform to study GBM but will serve as invaluable tools for drug screens for precision medicine.

概括多形性胶质母细胞瘤 (GBM) 是成人中最致命的原发性脑肿瘤，5 年生存率为低于5%。 GBM 是一种高度血管化和致命性脑肿瘤，其细胞层次结构包含自我更新和抗放疗的致瘤性神经胶质瘤干细胞（GSC）。对分子的理解 GSC 在其天然环境中的调节对于药物开发至关重要。可用的体外模型患有缺乏功能性血管的重大障碍。脉管系统不仅对于保持肿瘤存活，同时创造一个平衡 GSC 动态的肿瘤微环境，实现自我更新和差异化。因此，迫切需要临床前肿瘤模型研究 GBM 肿瘤的进展和治疗耐药性质，从而有助于药物治疗 GBM治疗的发展。该探索性 (R21) 提案的主要目标是 (a) 开发临床相关的生物工程 3D 血管化 GBM 类器官模型，以及 (b) 利用它们来询问 GBM 病理学。具体来说，3D生物打印方法将用于设计可灌注血管网络在类脑细胞外基质中嵌入 GSC 类器官。这种印刷结构将具有潜力提供生理上相似的生物物理和生化微环境以及血管周围的生态位促进干性线索的维持以及 GSC 转化为分化的神经胶质瘤细胞。作为 GSC 消融代表了治疗 GBM 的一种潜在治疗方法，这些生物工程 GBM 模型可用于了解 GSC 在模拟其微环境中的分子调控原生环境。预计这些 3D 生物打印血管化 GBM 模型不仅可以作为研究 GBM 的强大平台，也将成为精准医学药物筛选的宝贵工具。