Calcium Signalling Among Non-Neuronal Brain Cells

非神经元脑细胞中的钙信号传导

• 批准号: 6792752
• 负责人: Maiken Nedergaard
• 金额: $ 31.3万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6792752
• 关键词: astrocytes; calcium flux; capillary bed; estrogens; gap junctions; guanosinetriphosphatase activating protein; hormone regulation /control mechanism; laboratory rat; meninges; neocortex; neurons; progesterone; vascular endothelium

In previous studies, we have reported that calcium waves among gap junction-coupled glia may form the cellular substrate for spreading depression in vivo. Recently, we have noted that calcium waves initiated in astrocytes in slices can propagate to brain endothelial and meningeal cells; all of these cell types express connexin43, which may allow their mutual heterotypic syncytial interaction through homotypic gap junctions. On this basis, we propose to test the hypothesis that astrocytic calcium waves may thereby invade the brain by propagating along the capillary vasculature, as well as through the astrocytic syncytium. These experiments will test the possibility that endothelial calcium waves may follow the venular endothelium to invade the meningeal vasculature, thereby recruiting both meningeal cells and trigeminal sensory afferents. This proposed pathway, by bypassing and traversing the restrictive barrier of the pia limitans, would permit the recruitment of both the meningeal vasculature and its trigeminal sensory afferents into parenchymal waves of spreading depression. We propose here that this scenario might operationally model the initiation of migraine headache in adults. In parallel experiments, we will also follow-up our recent observation of a steroid-induced accentuation of astrocytic calcium signaling, by asking whether calcium signaling among non-neuronal brain cell types may be modulated by gonadal steroids. In particular, we seek to determine whether the cyclical female hormones estrogen and progesterone potentiate signaling from astrocytes to endothelial cells, and if so, whether the likelihood of meningovascular recruitment into a parenchymal calcium wave is thereby increased. This pathway might account for much of the symptomatology of migraine headache, while steroidal accentuation of calcium signaling might account for the cyclicity of migraine occurrence. The long-distance multicellular calcium signaling pathway that we propose, and its attendant hormonal regulation, suggests immediately testable strategies for its abrogation.

在以前的研究中，我们已经报道了缝隙连接偶联胶质细胞之间的钙波可能形成体内扩散性抑制的细胞基质。 最近，我们已经注意到，在星形胶质细胞切片中启动的钙波可以传播到脑内皮细胞和脑膜细胞;所有这些细胞类型表达连接蛋白43，这可能使它们通过同型间隙连接相互异型合胞体相互作用。 在此基础上，我们提出的假设，星形胶质细胞钙波可能因此侵入大脑传播沿着毛细血管系统，以及通过星形胶质细胞合胞体。 这些实验将测试内皮钙波可能跟随小静脉内皮侵入脑膜血管系统，从而招募脑膜细胞和三叉神经感觉传入的可能性。 这一拟议的途径，通过绕过和穿越软脑膜界的限制性屏障，将允许招募脑膜血管和三叉神经感觉传入到实质波的扩散性抑制。 我们建议在这里，这种情况下可能操作模型的开始偏头痛的成年人。 在平行实验中，我们还将跟进我们最近观察到的类固醇诱导的星形胶质细胞钙信号的加重，通过询问非神经元脑细胞类型之间的钙信号是否可以由性腺类固醇调节。 特别是，我们试图确定是否周期性的女性激素雌激素和孕激素增强信号从星形胶质细胞到内皮细胞，如果是这样的话，是否脑膜血管招募到实质钙波的可能性，从而增加。这一途径可能是偏头痛发病机制的主要原因，而钙信号的类固醇增强可能是偏头痛发生的周期性原因。我们提出的长距离多细胞钙信号通路及其伴随的激素调节，表明立即可测试的策略，其废除。