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.

项目摘要/摘要 胶质母细胞瘤（GBM，IV级神经胶质瘤）是最常见，最致命的原发性脑肿瘤之一 影响儿童和成人。 GBM与死亡率显着升高有关，并且没有 尽管有许多先前的临床试验，但患者可用于患者的有效疗法。相信更好 了解调节大脑中GBM细胞特性的细胞类型和因素可以提供新颖的 对病理学的见解，并揭示了治疗GBM患者的新治疗靶标。主要目标 R21提案是阐明人类GABA能神经元在调节的增殖和存活中的作用 人类GBM球体和人类诱导的GBM细胞使用创新的共培养方法 多能干细胞（IPSC）衍生的端脑器官（Organoid-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 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信及其影响 关于肿瘤细胞存活和增殖的通信。我们的具体假设是GABA能神经元形成 与GBM - 甲状腺嵌合体中肿瘤细胞的功能突触，以促进肿瘤细胞增殖或生存 通过GABA介导的肿瘤细胞去极化。检验该假设的具体目的是（1）确定 GABA能神经元是否与GBM细胞建立功能突触以调节肿瘤生长和存活率 （2）确定反式突触信号蛋白在调节肿瘤生长和存活中的作用。全面的， 我们希望这项研究将提高我们对涉及的细胞和分子机制的理解 人类大脑中GBM细胞特性的调节，并为研究 在人类脑样环境中，人脑肿瘤与人神经元的相互作用。