The Sulfur/Glutamate Circuitry in the Neuroimmune System

描述(申请人提供)：在大脑中，硫代谢体现了代谢协作的原理，为细胞提供了甲基化反应(S-腺苷蛋氨酸)、抗氧化能力(谷胱甘肽)、信号转导(硫化氢)和细胞体积调节(牛磺酸)的四种关键试剂。硫代谢的一个重要中间体是同型半胱氨酸，当同型半胱氨酸水平升高时，它与几种神经和其他疾病有关，包括阿尔茨海默病。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相交，即谷氨酸-谷氨酰胺循环，谷氨酸-谷氨酰胺循环是谷氨酸能突触传递的基础。协调氧化还原稳态和谷氨酸清除的失调分别导致氧化应激和兴奋毒性，是包括阿尔茨海默病在内的几种神经疾病的共同病理线索。我们一直在我们的实验室阐明基于同型半胱氨酸的氧化还原动态平衡的调节，并建议扩大这些研究，以检验星形胶质细胞和神经元硫代谢的相互依赖及其受外部刺激的调节。谷氨酸、β淀粉样蛋白(A？)和体积变化通过解决以下特定目标。(I)我们将确定A？对抗氧化剂和谷氨酸清除能力的潜在作用机制，并确定对A？刺激做出反应的硫醇蛋白质组。(Ii)我们将评估基于谷氨酸的信号对T细胞功能的影响，以及T细胞衍生细胞因子调节星形胶质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来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，并确定其如何受体积变化和谷氨酸的调节。我们的研究将在神经保护的背景下解决我们对基于谷氨酸的信号、基于牛磺酸的渗透调节和星形胶质细胞硫运输之间的主要差距，并与从阿尔茨海默病到低钠血症的一系列病理相关的生物医学相关。 与公共健康相关：在大脑中，硫代谢调节抗氧化能力和细胞体积调节，并与基于谷氨酸的信号密切相关。我们建议研究星形胶质细胞、神经元和T细胞在正常和神经毒性条件下执行这些关键功能时的代谢相互依赖关系。

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.