Glioma Circuitry: Bridging Systems Neuroscience and Cancer

神经胶质瘤回路：连接系统神经科学和癌症

• 批准号: 9553402
• 负责人: Michelle Monje-Deisseroth
• 金额: $ 109.55万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9553402
• 关键词: Action Potentials; Adult; Brain; Brain Neoplasms; Calcium; Cancer Biology; Cell Proliferation; Cell Survival; Cells; Cessation of life; Child; Dependence; Diffuse intrinsic pontine glioma; Disease; Electrophysiology (science); Excitatory Synapse; Exhibits; Gap Junctions; Glioblastoma; Glioma; Glutamates; Growth; Human; Image; Intervention; Invaded; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Maps; Mediating; Membrane; Modernization; Molecular; Monitor; Mus; Nervous system structure; Neurons; Neurosciences; Outcome; Patients; Pattern; Research; Resistance; Signal Transduction; Synapses; System; Testing; Therapeutic; Therapeutic Intervention; Time; Work; Xenograft Model; awake; cancer cell; effective therapy; neural circuit; neuronal circuitry; new therapeutic target; next generation; optogenetics; release of sequestered calcium ion into cytoplasm; response; tool; tumor; tumor microenvironment

Project Summary High-grade gliomas, such as glioblastoma and diffuse intrinsic pontine glioma (DIPG), represent the leading cause of brain cancer-related death for both adults and children. Among the most intractable human cancers, these tumors are quick to recur and nearly impossible to eliminate. A fundamental shift in our approach to glioma therapy is in dire need. My research group has recently discovered that gliomas grow in response to nervous system activity and further that gliomas exhibit a surprisingly profound dependency on these neuronal mechanisms. Our cellular and molecular work has led us to the startling realization that gliomas functionally integrate into electrically active neuronal circuits through bona fide neuron to glioma synapses, and the effects of neuron to glioma signaling may be amplified throughout the tumor via a network of recently described glioma to glioma gap junction-mediated connections. We hypothesize that this cooperative, interconnected network of glioma cells and neurons is fundamental to high-grade glioma progression and therapy resistance. Effective therapy for this lethal group of brain cancers may therefore require targeting not only molecular mechanisms of cell proliferation and survival, but also patterns of membrane depolarization and structural connections between cells. In order to study this, a shift from the predominant cellular/molecular perspective of cancer biology to a systems neuroscience approach is required. In the present proposal, we seek to apply the powerful next-generation tools of modern systems neuroscience together with patient-derived orthotopic xenograft models of high-grade gliomas to map, monitor and control the circuit dynamics of high-grade gliomas at progressive time points during the course of the disease. Optogenetic control of neuronal action potentials and of glioma membrane depolarizations together with live calcium imaging in awake, behaving mice will elucidate the functional significance of various temporal and spatial patterns of glioma circuit activity to glioma growth. Molecular interventions aimed at disassembling the various components of the neuronal- glioma network will discern the relative contribution of each and identify novel therapeutic targets. Ultimately, therapeutically modulating malignant circuit activity may prove transformative for high-grade glioma outcomes.!

项目摘要 高级别胶质瘤，如胶质母细胞瘤和弥漫性内在脑桥胶质瘤（DIPG），代表了主要的神经胶质瘤。 成人和儿童的脑癌相关死亡原因。在最难治的人类癌症中， 这些肿瘤很快复发，几乎不可能消除。我们的方法发生了根本性的转变， 神经胶质瘤治疗是迫切需要的。我的研究小组最近发现神经胶质瘤的生长是对 神经系统活动，而且神经胶质瘤表现出对这些神经元 机制等我们的细胞和分子工作使我们惊人地认识到，胶质瘤在功能上 通过真正的神经元到胶质瘤突触整合到电活性神经元回路中， 神经元到神经胶质瘤的信号传导可能通过最近描述的神经元网络在整个肿瘤中被放大。 胶质瘤与胶质瘤间隙连接介导的连接。我们假设这种合作的，相互联系的 神经胶质瘤细胞和神经元的网络是高级别神经胶质瘤进展和治疗抗性的基础。 因此，针对这组致命脑癌的有效治疗可能不仅需要分子靶向 细胞增殖和存活的机制，以及膜去极化和结构的模式 细胞之间的联系。为了研究这一点，从主要的细胞/分子角度的转变 将癌症生物学转化为系统神经科学方法是必需的。在目前的建议中，我们寻求适用 现代系统神经科学的强大下一代工具，以及患者源性原位 高级别胶质瘤的异种移植模型，以绘制、监测和控制高级别胶质瘤的电路动力学。 神经胶质瘤在疾病过程中的进行性时间点。神经元活动的光遗传学控制 脑胶质瘤细胞膜去极化电位和肝钙显像在清醒、行为 小鼠将阐明胶质瘤回路活动的各种时间和空间模式的功能意义 神经胶质瘤的生长分子干预旨在分解神经元的各种成分- 神经胶质瘤网络将辨别每个神经胶质瘤的相对贡献并识别新的治疗靶点。最后， 治疗性调节恶性回路活动可能证明对高级别胶质瘤具有变革性 结果！