Targeting Neuron-Microglia Interactions at the Margin of Glioma

靶向神经胶质瘤边缘的神经元-小胶质细胞相互作用

• 批准号: 10156376
• 负责人: Alexander Goldberg
• 金额: $ 4.61万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2025-06-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10156376
• 关键词: Acute; Antiepileptic Agents; Automobile Driving; Binding; Brain; Brain Neoplasms; CCL3 gene; CXCL2 gene; Calcium; Calcium Signaling; Calcium ion; Cations; Cell Density; Cell Proliferation; Cells; Chronic; Communication; Data; Electroencephalography; Epilepsy; Epileptogenesis; Event; Exhibits; Family; Frequencies; GTP-Binding Protein alpha Subunits, Gs; Glioma; Growth; Histologic; Image; In Situ Hybridization; Inflammatory; Inflammatory Response; Injections; Interleukin-1 beta; Interleukin-6; Link; Measurement; Measures; Mediating; Microglia; Monitor; Mus; Neuroglia; Neurons; P2X-receptor; PDGFA gene; Pathologic; Patients; Penetrance; Process; Purines; Purinoceptor; Reporting; Role; Seizures; Sensory; Severities; Signal Transduction; Stimulus; TNF gene; TP53 gene; Testing; Vibrissae; angiogenesis; barrel cortex; cancer initiation; cell growth; cohesion; cytokine; design; experience; in vivo calcium imaging; in vivo imaging; inhibitor/antagonist; mRNA Expression; migration; neuronal cell body; receptor; receptor expression; response; tumor; tumor microenvironment; tumor progression

PROJECT SUMMARY/ABSTRACT Recent studies have revealed that crosstalk between glioma cells and the brain microenvironment is a crucial regulator of cancer initiation and progression. A vast majority of glioma patients suffer from seizures, and this pathological neuronal activity has been proposed to contribute to increased glioma growth and proliferation. While some have hypothesized that neurons may be directly altering glioma cell activity, this proposal investigates whether a more prominent consequence of pathological neuronal activity is to cause activation of microglia, whose pro-inflammatory response contributes to glioma growth. This proposal will investigate glioma-induced changes in neuronal and microglial activity and whether neuronal activity, microglia, and glioma cells are mechanistically linked in driving cancer progression. Microglia have been separately implicated in both epileptogenesis and glioma growth. Neurons communicate directly with microglia through secreted purines, such as ATP, acting on microglial purinergic receptors. This ATP binding causes microglial activation, and activated microglia have been shown to stimulate glioma cell growth, enhance invasiveness and migration of glioma cells, and cause angiogenesis. P2RX7 is a well-studied purinergic receptor present on microglia, shown in preliminary data to be highly expressed in the tumor microenvironment. In aim 1, I will use whisker stimulation with simultaneous in-vivo imaging of neuronal and microglial calcium activity to determine if the presence of glioma causes pathological stimulus-evoked responses in neurons and microglia. In aim 2, I will utilize electroconvulsive seizure (ECS) induction to determine the effect of seizures, a known instance of pathological neuronal activity, on microglial expression of inflammatory cytokines as well as on glioma growth. In both aims I will administer Brilliant Blue G (BBG), a selective P2RX7 inhibitor with known CNS penetrance to interrogate if these effects are mediated through purinergic signaling between neurons and microglia.

项目概要/摘要 最近的研究表明，神经胶质瘤细胞和大脑微环境之间的串扰是一种 癌症发生和进展的重要调节因子。绝大多数神经胶质瘤患者患有癫痫发作，并且 这种病理性神经元活动被认为有助于增加神经胶质瘤的生长和增殖。 虽然有些人假设神经元可能直接改变神经胶质瘤细胞的活性，但这一提议 研究病理性神经元活动的一个更突出的后果是否是引起激活 小胶质细胞，其促炎症反应有助于神经胶质瘤的生长。本提案将调查 神经胶质瘤引起的神经元和小胶质细胞活性的变化以及神经元活性、小胶质细胞是否 神经胶质瘤细胞在驱动癌症进展方面存在机械联系。小胶质细胞已被单独 与癫痫发生和神经胶质瘤生长有关。神经元通过以下方式直接与小胶质细胞通讯 分泌嘌呤，如ATP，作用于小胶质细胞嘌呤能受体。这种 ATP 结合导致小胶质细胞 激活和激活的小胶质细胞已被证明可以刺激神经胶质瘤细胞生长，增强侵袭性和 胶质瘤细胞的迁移，并引起血管生成。 P2RX7 是一种经过充分研究的嘌呤能受体，存在于 初步数据显示小胶质细胞在肿瘤微环境中高度表达。在目标 1 中，我将使用 胡须刺激，同时对神经元和小胶质细胞钙活性进行体内成像，以确定是否 神经胶质瘤的存在会引起神经元和小胶质细胞的病理刺激诱发反应。在目标2中，我会 利用电惊厥癫痫发作 (ECS) 诱导来确定癫痫发作的影响，这是一种已知的例子 病理神经元活动、小胶质细胞炎症细胞因子的表达以及神经胶质瘤的生长。 在这两个目标中，我将使用 Brilliant Blue G (BBG)，这是一种选择性 P2RX7 抑制剂，具有已知的中枢神经系统外显率 询问这些效应是否是通过神经元和小胶质细胞之间的嘌呤能信号传导介导的。