Store-operated channels in the nervous system

星形胶质细胞是脑内主要的神经胶质细胞类型，调节着脑的多种功能 包括神经发育、神经递质的清除和血流的调节。最近 有证据表明星形胶质细胞在调节神经元兴奋性方面也起重要作用， 突触传递通过分泌多种神经活性因子，包括促炎因子 细胞因子这些细胞因子引起神经元和神经胶质功能的大量变化，包括 Ca 2+信号传导和突触传递的改变，这与病理学有关， 神经性疼痛特别是，神经损伤后，炎症细胞因子包括TNFα， IL-1 β和IL-6由神经胶质细胞快速产生，以增强兴奋性突触的强度。 在脊髓中的伤害感受回路中的传递并诱发慢性疼痛。而小胶质细胞， 大脑中的巨噬细胞样细胞类型在这方面受到了极大的关注。 在这一过程中，星形胶质细胞的作用和调节这一过程的细胞检查点不太好 明白我们的初步研究结果表明，钙库操作的钙释放激活的钙 （CRAC）通道是星形胶质细胞中嘌呤能诱发的Ca 2+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 一系列促炎细胞因子和趋化因子。基于这些证据，我们假设， CRAC通道是神经病理性星形胶质细胞介导的神经炎症的重要调节因子 痛苦我们提出了三个具体目标来解决这个假设：1）定义CRAC的作用 激动剂诱发的Ca 2+升高和星形胶质细胞炎症输出的通道，2） 确定CRAC通道介导的炎性细胞因子对炎症的贡献。 脊髓背角突触传递的适应不良增强 神经损伤，和3）检查CRAC通道介导的炎性神经损伤的体内相关性。 从星形胶质细胞产生细胞因子用于神经性疼痛。我们将使用以下方法来处理这些问题： 星形胶质细胞中CRAC通道蛋白的基因敲除、生化和转录组分析 细胞因子合成，切片电生理学，Ca 2+成像和行为分析。结果 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，并帮助寻求开发新的星形胶质细胞靶向治疗影响脑功能的病理性疾病。

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.