Regulation of glioblastoma cells by GABAergic neurons in human organoid-tumor chimeras

人类器官-肿瘤嵌合体中 GABA 能神经元对胶质母细胞瘤细胞的调节

• 批准号: 10643308
• 负责人: Oleksandr Shcheglovitov
• 金额: $ 21.58万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-06 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643308
• 关键词: Adult; Affect; Brain; Brain Neoplasms; Cell Adhesion Molecules; Cell Communication; Cell Proliferation; Cell Survival; Cells; Central Nervous System; Chemical Synapse; Chemicals; Child; Chimera organism; Clinical Trials; Coculture Techniques; Communication; Diagnosis; Electrophysiology (science); Environment; Ethics; Excitatory Synapse; Exhibits; Functional disorder; Future; GABA Receptor; Gene Expression; Glioblastoma; Glioma; Glutamates; Goals; Growth; Growth Factor; Human; Individual; Malignant neoplasm of central nervous system; Measures; Mediating; Membrane Potentials; Molecular; Mus; Neurons; Neurosciences; Normal Cell; Organoids; Pathogenesis; Pathology; Patients; Pharmacology; Primary Brain Neoplasms; Proliferating; Property; Public Health; Regulation; Research; Role; Signal Transduction; Signaling Protein; Slice; Specificity; Synapses; System; Techniques; Testing; Tumor Promotion; Tumor Tissue; Work; cancer cell; cell type; effective therapy; excitatory neuron; experimental study; gamma-Aminobutyric Acid; human stem cells; improved; in vivo; induced pluripotent stem cell; innovation; insight; mortality; neoplastic cell; nerve stem cell; neuroligin 1; neuroligin 3; neuroregulation; new therapeutic target; novel; optogenetics; patch clamp; pediatric patients; postsynaptic; presynaptic neurons; rabies viral tracing; response; single-cell RNA sequencing; stem cells; therapeutic target; tool; tumor; tumor growth

PROJECT SUMMARY/ABSTRACT Glioblastoma (GBM, WHO Grade IV glioma) is one of the most common and deadliest primary brain tumors that affects both children and adults. GBM is associated with significantly elevated mortality, and there are no effective therapies available for patients despite many previous clinical trials. It is believed that a better understanding of the cell types and factors regulating GBM cell properties in the brain could provide novel insights into the pathology and reveal new therapeutic targets for treating GBM patients. The main goal of this R21 proposal is to elucidate the role of human GABAergic neurons in regulating the proliferation and survival of GBM cells in the brain using an innovative co-culture approach of human GBM spheroids and human induced pluripotent stem cell (iPSC)-derived telencephalic organoids (organoid-GBM chimera). To achieve this goal, we will use the most advanced neuroscience tools and techniques, including human stem cell-derived brain organoids, optogenetics, rabies virus tracing, and single-cell RNA sequencing, to characterize the communication between GABAergic neurons and tumor cells in organoid-GBM chimera and the effects of this communication on tumor cell survival and proliferation. Our specific hypothesis is that GABAergic neurons form functional synapses with tumor cells in GBM-organoid chimeras to promote tumor cell proliferation or survival via GABA-mediated depolarization of tumor cells. The specific aims to test this hypothesis are (1) to determine whether GABAergic neurons establish functional synapses with GBM cells to regulate tumor growth and survival and (2) to determine the role of trans-synaptic signaling proteins in regulating tumor growth and survival. Overall, we expect that this study will advance our understanding of the cellular and molecular mechanisms involved in the regulation of GBM cell properties in the human brain and provide a novel framework for studying the interactions of human brain tumors with human neurons in a human brain-like environment.

项目概要/摘要 胶质母细胞瘤（GBM，世界卫生组织 IV 级胶质瘤）是最常见和最致命的原发性脑肿瘤之一 影响儿童和成人。 GBM 与死亡率显着升高相关，并且没有证据表明 尽管之前进行过许多临床试验，但仍可为患者提供有效的治疗方法。相信有更好的 了解大脑中调节 GBM 细胞特性的细胞类型和因素可以提供新的思路 深入了解病理学并揭示治疗 GBM 患者的新治疗靶点。此次活动的主要目标 R21提案旨在阐明人类GABA能神经元在调节细胞增殖和存活中的作用 使用人类 GBM 球体和人类诱导的创新共培养方法在大脑中的 GBM 细胞 多能干细胞（iPSC）衍生的端脑类器官（类器官-GBM嵌合体）。为了实现这一目标，我们 将使用最先进的神经科学工具和技术，包括人类干细胞衍生的大脑 类器官、光遗传学、狂犬病病毒追踪和单细胞 RNA 测序，以表征 类器官-GBM嵌合体中GABA能神经元和肿瘤细胞之间的通讯及其影响 肿瘤细胞存活和增殖的通讯。我们的具体假设是 GABA 能神经元形成 GBM-类器官嵌合体中与肿瘤细胞的功能性突触促进肿瘤细胞增殖或存活 通过 GABA 介导的肿瘤细胞去极化。检验该假设的具体目标是 (1) 确定 GABA能神经元是否与GBM细胞建立功能性突触来调节肿瘤生长和存活 (2)确定跨突触信号蛋白在调节肿瘤生长和存活中的作用。全面的， 我们期望这项研究将增进我们对相关细胞和分子机制的理解 人脑中 GBM 细胞特性的调节，并为研究 GBM 细胞特性提供了一个新的框架 在类似人脑的环境中，人脑肿瘤与人神经元的相互作用。