The Sulfur/Glutamate Circuitry in the Neuroimmune System

描述（由申请者提供）：在大脑中，硫代谢体现了代谢合作原则，并为细胞提供了甲基化反应（s -腺苷甲硫氨酸）、抗氧化能力（谷胱甘肽）、信号传导（H2S）和细胞体积调节（牛磺酸）的四种主要试剂。硫代谢的重要中间体是同型半胱氨酸，其水平升高与包括阿尔茨海默病在内的几种神经系统疾病和其他疾病有关。谷胱甘肽和牛磺酸的合成途径需要星形胶质细胞和神经元之间的代谢整合，并与大脑中另一个主要循环——谷氨酸-谷氨酰胺循环相交，谷氨酸-谷氨酰胺循环是谷氨酸能突触传递的基础。氧化还原稳态和谷氨酸清除的协调失调分别导致氧化应激和兴奋性毒性，是包括阿尔茨海默病在内的几种神经系统疾病的共同病理线索。在我们的实验室中，我们已经阐明了基于同型半胱氨酸的氧化还原稳态的调节，并建议扩大这些研究，以检查星形胶质细胞和神经元的硫代谢共同依赖及其通过外部刺激（即谷氨酸，β淀粉样蛋白（A¿）和体积变化）的调节，通过解决以下具体目标。(i)我们将确定A¿影响抗氧化和谷氨酸清除能力的潜在机制，并确定对A¿刺激有反应的硫醇蛋白质组。（ii）我们将评估基于谷氨酸的信号传导对T细胞功能的影响，以及T细胞来源的细胞因子调节星形细胞谷氨酸清除的机制。（iii）我们将通过使用x射线荧光显微镜的活细胞成像确定牛磺酸池的位置，阐明其在星形胶质细胞和神经元中的合成途径，并确定它是如何通过体积变化和谷氨酸调节的。我们的研究将解决我们对星形胶质细胞中基于谷氨酸的信号传导、基于牛磺酸的渗透调节和硫运输之间的联系的理解中的主要空白，这些联系与阿尔茨海默病和低钠血症等一系列疾病的生物医学相关的神经保护有关。

DESCRIPTION (provided by applicant): In brain, sulfur metabolism exemplifies the principle of metabolic cooperation and furnishes cells with four major reagents critical for methylation reactions (S-adenosylmethionine), antioxidant capacity (glutathione), signaling (H2S), and cell volume regulation (taurine). An important intermediate in sulfur metabolism is homocysteine, which at elevated levels, is correlated with several neurological and other disorders including Alzheimer's disease. The pathways for glutathione and taurine syntheses require metabolic integration between astrocytes and neurons and intersect with yet another major cycle in brain, the glutamate-glutamine cycle that underlies glutamatergic synaptic transmission. Coordinate dysregulation of redox homeostasis and glutamate clearance leading to oxidative stress and excitotoxicity respectively, is a common thread in the pathologies of several neurological disorders, including Alzheimer's disease. We have been elucidating the regulation of homocysteine-based redox homeostasis in our laboratory and propose to broaden these studies to examine the sulfur metabolic co-dependence of astrocytes and neurons and its modulation by external stimuli, viz. glutamate, beta amyloid (A¿), and volume change by addressing the following specific aims. (i) We will determine the mechanisms underlying A¿ effects on antioxidant and glutamate clearance capabilities and identify the thiol proteome that responds to A¿ stimulation. (ii) We will assess the effects of glutamate-based signaling on T cell function and the mechanism of T cell-derived cytokines on modulating astrocytic glutamate clearance. (iii) We will determine where taurine pools are located by live cell imaging using X-ray fluorescence microscopy, elucidate the pathway for its synthesis in astrocytes and neurons and determine how it is modulated by volume alteration and by glutamate. Our studies will address major gaps in our understanding of the links between glutamate-based signaling, taurine-based osmoregulation and sulfur trafficking in astrocytes in the context of neuroprotection with biomedical relevance to a range of pathologies from Alzheimer's disease to hyponatremia. PUBLIC HEALTH RELEVANCE: In brain, sulfur metabolism modulates antioxidant capacity and cell volume regulation and is intimately interlinked with glutamate-based signaling. We propose to study the metabolic interdependence between astrocytes, neurons and T cells in performing these critical functions under normal and neurotoxic conditions.