Targeting Neuron-Microglia Interactions at the Margin of Glioma

项目摘要/摘要 最近的研究表明，胶质瘤细胞和大脑微环境之间的串扰是一种 癌症发生和发展的关键调节因子。绝大多数神经胶质瘤患者都患有癫痫，而且 这种病理性神经元活动被认为是导致胶质瘤生长和增殖增加的原因。 虽然有些人假设神经元可能直接改变了胶质瘤细胞的活动，但这一提议 研究病理性神经元活动的一个更显著的后果是否是导致 小胶质细胞，其促炎反应有助于胶质瘤的生长。这项提案将调查 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、 而胶质瘤细胞在推动癌症进展方面存在机械联系。小胶质细胞已经被分开 与癫痫的发生和胶质瘤的生长有关。神经元通过以下途径与小胶质细胞直接通信 分泌的嘌呤，如三磷酸腺苷，作用于小胶质细胞的嘌呤能受体。这种三磷酸腺苷结合导致小胶质细胞 激活和激活的小胶质细胞被证明可以刺激胶质瘤细胞的生长，增强侵袭力和 胶质瘤细胞的迁移，并引起血管生成。P2RX7是一种研究广泛的嘌呤能受体，目前存在于 小胶质细胞，初步数据显示在肿瘤微环境中高表达。在目标1中，我将使用 晶须刺激同时成像神经元和小胶质细胞钙活性以确定是否 胶质瘤的存在会引起神经元和小胶质细胞的病理性刺激诱发反应。在《目标2》中，我会 利用电惊厥(ECS)诱导来确定癫痫发作的影响，这是一个已知的例子 病理神经元活性、对小胶质细胞炎性细胞因子的表达以及对胶质瘤生长的影响。 在这两个目标中，我将使用灿烂蓝G(BBG)，这是一种选择性的P2RX7抑制剂，具有已知的中枢神经系统通透性 询问这些效应是否通过神经元和小胶质细胞之间的嘌呤能信号来调节。

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.