Targeting Neuron-Microglia Interactions at the Margin of Glioma

项目总结/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个重要的因素。 是癌症发生和发展的重要调节因子。绝大多数神经胶质瘤患者患有癫痫发作， 已经提出这种病理性神经元活性有助于神经胶质瘤生长和增殖的增加。 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 小胶质细胞，其促炎反应有助于胶质瘤生长。该提案将调查 神经胶质瘤诱导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， 和神经胶质瘤细胞在驱动癌症进展方面有机械联系。小胶质细胞已经被分别 与癫痫发生和神经胶质瘤生长有关神经元直接与小胶质细胞沟通， 分泌的嘌呤，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 活化和活化的小胶质细胞已经显示刺激神经胶质瘤细胞生长，增强侵袭力， 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 小胶质细胞，初步数据显示在肿瘤微环境中高度表达。在目标1中，我将使用 晶须刺激与神经元和小胶质细胞钙活性的同时体内成像，以确定是否 神经胶质瘤的存在引起神经元和小胶质细胞中的病理性刺激诱发反应。在目标2中，我将 利用电惊厥发作（ECS）诱导来确定癫痫发作的影响，这是一个已知的 病理性神经元活性，对炎性细胞因子的小胶质细胞表达以及对胶质瘤生长的影响。 在这两个目标中，我将给予亮蓝G（BBG），一种选择性P2RX 7抑制剂，具有已知的CNS抑制率， 询问这些作用是否通过神经元和小胶质细胞之间的嘌呤能信号传导介导。

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.