Store-operated channels in the nervous system

星形胶质细胞是大脑中主要的神经胶质细胞类型，调节多种大脑功能。 包括神经发育、神经递质的清除和血流的调节。近期 有证据表明，星形胶质细胞在调节神经元兴奋性和 分泌多种神经活性因子包括促炎因子的突触传递 细胞因子。这些细胞因子引起神经元和神经胶质功能的一系列变化，包括 钙信号和突触传递的变化，这与病理有关，如 神经性疼痛。尤其是神经损伤后，包括肿瘤坏死因子α在内的炎性细胞因子， 神经胶质细胞迅速产生IL-1β和IL-6，增强兴奋性突触的强度 在脊髓的伤害性回路中传递，并引起慢性疼痛。而小胶质细胞，一个 在这方面，大脑中的巨噬细胞样细胞类型受到了最大程度的关注 在这一过程中，星形胶质细胞的作用以及调节这一过程的细胞检查点就不太好了 明白了。我们的初步发现表明，商店操作的钙离子释放激活了钙离子 (CRAC)通道是星形胶质细胞嘌呤能诱发的钙信号的主要机制。 它们在脊髓星形胶质细胞中的激活强烈刺激广泛的转录和分泌 促炎症细胞因子和趋化因子的范围。根据这一证据，我们假设 CRAC通道是神经病变中星形胶质细胞介导的神经炎症的重要调节因子 疼痛。我们提出了三个具体目标来解决这一假设：1)界定CRAC的角色 激动剂引起的钙离子升高和星形胶质细胞炎症输出的通道，2) 确定CRAC通道介导炎性细胞因子在血管内皮细胞损伤中的作用 大鼠脊髓背角突触传递的非适应性增强 神经损伤，以及3)检测CRAC通道介导的炎症反应的体内相关性 神经病理性疼痛的星形胶质细胞产生的细胞因子。我们将使用以下工具来解决这些问题 星形胶质细胞CRAC通道蛋白基因敲除、生化和转录组分析 包括细胞因子合成、切片电生理学、钙成像和行为分析。结果来自 这些研究将促进我们对CRAC通道的生理作用的理解 调节星形胶质细胞介导的神经炎症，并帮助探索针对影响大脑功能的病理性疾病开发新的星形胶质细胞靶向疗法。

Astrocytes comprise the major glial cell type in the brain and regulate numerous brain functions including neural development, clearance of neurotransmitters, and regulation of blood flow. Recent evidence indicates that astrocytes also play important roles in regulating neuronal excitability and synaptic transmission by secreting a variety of neuroactive factors including proinflammatory cytokines. These cytokines evoke a vast array of changes in neuronal and glial function including alterations in Ca2+ signaling and synaptic transmission, which implicated in pathologies such as neuropathic pain. In particular, following nerve injury, inflammatory cytokines including TNFα, IL1β , and IL-6 are rapidly produced by glial cells to enhance the strength of excitatory synaptic transmission in nociceptive circuits in the spinal cord and induce chronic pain. While microglia, a macrophage-like cell type in the brain have received the lion's share of the attention in this process, the role of astrocytes and the cellular checkpoints that regulate this process are less well understood. Our preliminary findings indicate that store-operated Ca2+ release-activated Ca2+ (CRAC) channels are a major mechanism for purinergic-evoked Ca2+ signals in astrocytes and their activation in spinal astrocytes strongly stimulates the transcription and secretion of a wide range of proinflammatory cytokines and chemokines. Based on this evidence, we hypothesize that CRAC channels are essential regulators of astrocyte-mediated neuroinflammation in neuropathic pain. We propose three specific aims to address this hypothesis: 1) Define the role of CRAC channels for agonist-evoked Ca2+ elevations and the inflammatory output of astrocytes, 2) Determine the contributions of CRAC channel-mediated inflammatory cytokines for the maladaptive potentiation of synaptic transmission in the dorsal horn of the spinal cord following nerve injury, and 3) examine the in vivo relevance of CRAC channel-mediated inflammatory cytokine production from astrocytes for neuropathic pain. We will approach these questions using genetic knockouts of CRAC channel proteins in astrocytes, biochemical and transcriptome analysis of cytokine synthesis, slice electrophysiology, Ca2+ imaging, and behavioral analysis. Results from these studies will advance our understanding of the physiological role of CRAC channels for regulating astrocyte-mediated neuroinflammation and aid the quest for developing new astrocyte-targeted therapies for pathological diseases affecting brain function.