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: 10651769
• 负责人: Alexander Goldberg
• 金额: $ 5.27万
• 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/10651769
• 关键词: Acceleration; Acute; Antiepileptic Agents; Automobile Driving; Binding; Brain; Brain Neoplasms; CCL3 gene; CXCL2 gene; Calcium; Calcium Signaling; Calcium ion; Cell Density; Cell Proliferation; Cells; Chronic; Communication; Data; Electroencephalography; Epilepsy; Epileptogenesis; Event; Exhibits; Family; Frequencies; Glioma; Gliosis; Growth; Histologic; Image; In Situ Hybridization; Infiltration; 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; Proliferating; Purines; Purinoceptor; Reporting; Resected; Role; Seizures; Sensory; Severities; Signal Transduction; Stimulus; TNF gene; TP53 gene; Testing; Tumor Promotion; Vibrissae; angiogenesis; antagonist; barrel cortex; cancer initiation; cell growth; cytokine; design; epileptiform; experience; glial activation; in vivo calcium imaging; in vivo imaging; inhibitor; mRNA Expression; migration; neurotransmission; 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.

项目总结/文摘