POLYAMINE SIGNALING VIA GLIAL CONNEXIN-43 HEMICHANNELS IN RETINA

通过视网膜中的胶质连接蛋白 43 半通道进行多胺信号传导

• 批准号: 7960054
• 负责人: YURIY KUCHERYAVYKH
• 金额: $ 9.19万
• 依托单位: UNIVERSITY OF PUERTO RICO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7960054
• 关键词: Biomedical Research; Cells; Cessation of life; Computer Retrieval of Information on Scientific Projects Database; Connexin 43; Connexins; Data; Enzymes; Funding; Gap Junctions; Glaucoma; Glutamate Receptor; Glutamates; Grant; Institution; Intervention; N-Methyl-D-Aspartate Receptors; Neuroglia; Neurons; Photoreceptors; Physiological; Polyamines; Preparation; Puerto Rico; Research; Research Personnel; Resources; Retina; Retinal; Signal Transduction; Signaling Molecule; Source; Spermidine; Spermine; Techniques; Testing; Thick; United States National Institutes of Health; Work; excitotoxicity; ganglion cell; insight; kainate; receptor; retinal ischemia; retinal neuron

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The major glial cells in the retina, M¿ller cells, span the whole retinal thickness from photoreceptors to ganglion cells. M¿ller cells contact and even delimit all neuronal compartments and can release neuroactive substances to directly regulate neurons. One likely candidate to regulate retinal neuronal activity is the endogenous polyamine spermine (SPM). The polyamines spermine and spermidine (SPM/SPD) are predominantly located in M¿ller cells in the retina, but modulate many neuronal receptors and channels found on retinal neurons including AMPA, kainate, NMDA receptor channels and Kir channels. Our preliminary data demonstrate release of SPM/SPD from this glia to neuronal network under glial specific treatments. Our working hypothesis is that endogenous SPM acts as a signaling molecule between glial and neuronal cells in the retina: (i) SPM is accumulated and released from M¿ller (glial) cells, potentially through unapposed hemi-gap junctions (hemichannels) and (ii) acts simultaneously on several types of neuronal receptors and channels to modulate retinal neuronal networks. Using electrophysiological and immunocytochemical techniques, we propose to test this hypothesis by the following specific aims: Specific aim 1 To determine if M¿ller glial cells express the biosynthetic enzymes necessary for polyamine synthesis under physiological and pathophysiological conditions. Specific aim 2  To examine SPM flux potentially through connexin hemichannels or P2X7 receptors in retinal M¿ller (glial) cells. Specific aim 3  To determine the effect of spermine on glutamate receptors in isolated retinal neurons and in a retinal whole-mount preparation. The results of these studies will provide insight into spermine-dependent retinal activity and may ultimately result in interventions for glaucoma, retinas ischemia, glutamate excitotoxicity and subsequent neuronal death.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 视网膜中的主要神经胶质细胞，米勒细胞，横跨整个视网膜厚度 神经节细胞的光感受器。穆勒细胞接触甚至界定所有神经元 可以释放神经活性物质来直接调节神经元。一 调节视网膜神经元活动的可能候选者是内源性多胺精胺 （SPM）。多胺精胺和亚精胺 (SPM/SPD) 主要位于 视网膜中的米勒细胞，但调节许多神经元受体和通道 视网膜神经元包括 AMPA、红藻氨酸、NMDA 受体通道和 Kir 通道。我们的 初步数据表明 SPM/SPD 从该神经胶质细胞释放到神经元网络 胶质细胞特异性治疗。我们的工作假设是内源性 SPM 充当信号传导 视网膜神经胶质细胞和神经元细胞之间的分子：(i) SPM 积累和释放 来自穆勒（神经胶质）细胞，可能通过未并列的半间隙连接（半通道） (ii) 同时作用于多种类型的神经元受体和通道以进行调节 视网膜神经元网络。利用电生理学和免疫细胞化学技术， 我们建议通过以下具体目标来检验这一假设： 具体目标 1 确定 M¿ller 胶质细胞是否表达必需的生物合成酶 用于生理和病理生理条件下多胺的合成。 具体目标 2 检查可能通过连接蛋白半通道或 P2X7 的 SPM 通量 视网膜米勒（神经胶质）细胞中的受体。 具体目标 3 确定精胺对分离的谷氨酸受体的影响 视网膜神经元和视网膜整体制备物。 这些研究的结果将提供对精胺依赖性视网膜活动的深入了解和 最终可能导致青光眼、视网膜缺血、谷氨酸的干预 兴奋性毒性和随后的神经元死亡。