The Sulfur/Glutamate Circuitry in the Neuroimmune System

描述（由申请方提供）：在脑中，硫代谢阐明了代谢合作的原理，并使用对甲基化反应（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）至关重要的四种主要试剂使细胞活化。硫代谢中的一个重要中间体是同型半胱氨酸，其在升高的水平下与几种神经系统和其他疾病（包括阿尔茨海默病）相关。谷胱甘肽和牛磺酸合成的途径需要星形胶质细胞和神经元之间的代谢整合，并与脑中的另一个主要循环，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。分别导致氧化应激和兴奋性毒性的氧化还原稳态和谷氨酸清除的协调失调是包括阿尔茨海默病在内的几种神经系统疾病的病理学中的共同线索。我们已经阐明了在我们的实验室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的共同依赖性及其通过外部刺激的调制，即谷氨酸，β淀粉样蛋白（A？），并通过解决以下具体目标的体积变化。(i)我们将确定潜在的抗氧化剂和谷氨酸清除能力的影响的机制，并确定巯基蛋白质组，响应A？刺激。(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细胞衍生的细胞因子调节星形胶质细胞谷氨酸清除的机制。(iii)我们将确定牛磺酸池位于活细胞成像使用X射线荧光显微镜，阐明其在星形胶质细胞和神经元的合成途径，并确定它是如何调制的体积变化和谷氨酸。我们的研究将解决我们对基于谷氨酸的信号传导，基于牛磺酸的神经调节和星形胶质细胞中硫贩运之间联系的理解中的主要差距，这些联系与阿尔茨海默病和低钠血症等一系列病理学的生物医学相关性神经保护。 公共卫生相关性：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传导密切相关。我们建议研究正常和神经毒性条件下星形胶质细胞，神经元和T细胞在执行这些关键功能之间的代谢相互依赖性。

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.