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

• 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
• 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

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.

总结