POLYAMINE SIGNALING VIA GLIAL CONNEXIN-43 HEMICHANNELS IN RETINA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 视网膜中的主要神经胶质细胞，M？ler细胞，横跨整个视网膜厚度，从 神经节细胞的光感受器。M？ler细胞与所有神经元接触，甚至划定界限 并且可以释放神经活性物质来直接调节神经元。一 可能调节视网膜神经元活动的候选物质是内源性多胺精胺 (SPM)。多胺、精胺和亚精胺(SPM/SPD)主要分布在 视网膜中的M？ler细胞，但对许多神经元受体和通道进行调节 视网膜神经元包括AMPA通道、红藻氨酸通道、NMDA受体通道和KIR通道。我们的 初步数据显示SPM/SPD从该胶质细胞释放到神经元网络 神经胶质细胞的特殊治疗。我们的工作假设是，内源性SPM作为一种信号 视网膜内神经胶质细胞和神经细胞之间的分子：(1)SPM的积累和释放 来自M？ler(神经胶质)细胞，可能通过未对位的半缝隙连接(半通道) 和(Ii)同时作用于几种类型的神经元受体和通道以调节 视网膜神经网络。使用电生理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： 特异性目标1：确定M？ler神经胶质细胞是否表达必要的生物合成酶 用于在生理和病理生理条件下合成多胺。 特定目标2：潜在地通过连接蛋白半通道或P2X7检测SPM的通量 视网膜神经胶质细胞中的受体。 特异靶3测定精胺对大鼠心肌细胞谷氨酸受体的影响 视网膜神经元和视网膜整体贴装制剂。 这些研究的结果将为深入了解精胺依赖的视网膜活动和 可能最终导致对青光眼、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。

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.